{
"claim": "Karyoptosis, Apoptosis, Ferroptosis: An Amyotrophic Lateral Sclerosis Study of PubMed Literature",
"timestamp": "2026-07-24T20:39:19.078Z",
"settings": {
"mode": "Social",
"library": "PubMed",
"format": "Preprint",
"length": "Standard",
"rigor": "Strict",
"tagCloud": "on",
"breadth": 40,
"depth": 3,
"runs": 3,
"evalsPerRun": 1,
"autoExplore": false,
"smartFollowUp": true
},
"prompt_settings": {
"research_veridical_check": {
"name": "Research Veridical Verification",
"purpose": "Audits the final research response after quotes pass to ensure absolute veridicality, logical consistency, and zero hallucinated external knowledge.",
"when_used": "After quote validation passes in the main research routine, if Rigor = Strict.",
"content": "You are a strict QA Audit AI. Your job is to verify the RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"assistant_veridical_check": {
"name": "Assistant Veridical Verification",
"purpose": "Audits the assistant's response to ensure absolute veridicality and rule adherence.",
"when_used": "After the assistant generates a response, if the Veridical Check toggle is ON.",
"content": "You are a strict QA Audit AI. Your job is to verify the ASSISTANT_RESPONSE and RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"custom_datapoints_directive": {
"name": "Custom Datapoints Directive",
"purpose": "Specifies custom keys and extraction rules for the AI to include in the JSON block.",
"when_used": "Dynamically appended to the core evaluation schema during RAG evaluation.",
"content": "### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"lmp_death_switch\": Investigate if lysosomal rupture (LMP) serves as the common upstream temporal initiator for both karyoptosis and ferroptosis in motor neuron models.\n- \"p38_lipid_link\": Examine whether the p38 kinase/LaminB1 signaling axis, which governs karyoptosis, also regulates the expression or activity of ferroptosis-related proteins like GPX4 or ACSL4.\n- \"polypharmacy_validation\": Determine if simultaneous pharmacological blockade of p38 kinase and enhancement of lipid peroxidation scavenging provides synergistic rescue of motor neuron viability compared to monotherapy.\n- \"p38_bifurcation_hypothesis\": Investigate if phosphorylated LaminB1 or downstream p38 targets influence the recruitment of ELDR components (e.g., YOD1/UBXD1) to sites of lysosomal membrane permeabilization, potentially acting as a kinetic checkpoint between repair (lysophagy) and terminal karyoptosis.\n- \"mitochondrial_nuclear_crosstalk\": Explore whether mitochondrial-derived reactive oxygen species (ROS) acting on the p38/MK2 axis act as the decisive signal that shifts the cell from attempting lysosomal repair (lysophagy) to initiating LaminB1-mediated nuclear degradation (karyoptosis).\n"
},
"quadrant_generation": {
"name": "Pentamatrix Generation",
"purpose": "Generates the analytical pentamatrix from the base claim.",
"when_used": "Beginning of the Semmelweis mode workflow.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes\n\nINITIAL EVALUATION: CLAIM vs. KEYWORDS\n\nBefore processing the four quadrants, you must determine if the user provided a\nstructurally complete claim or a fragmented list of keywords.\n\n - If Full Claim: Act as a strict transcription engine.\n - If Keyword List / Fragment: Act as a Speculative Synthesis Engine.\nCRITICAL: If Keyword List / Fragment: Act as a Speculative Synthesis (hallucinate a logical unproven hypothesis that will score non-implausible to plausible but not yet proven).\n\nQUADRANT CONSTRAINTS\n\n0. RAW USER TEXT\n1. ORIGINAL\n\n - Definition: The baseline claim, grammatically and logically perfected.\n - Rule for Full Claims: Transcribe exactly as stated. Your ONLY modification\n is to fix spelling, punctuation, and grammar. If the input is a question,\n convert it into a declarative claim.\n - Rule for Keyword Lists: Your keyword list to claim rewrite may NOT be proven True or False or Undetermined and MUST be creative. You MUST NOT summarize the keywords. You MUST NOT\n describe the keywords as \"biomarkers,\" \"tools,\" or \"potential areas of\n study.\" You MUST synthesize the keywords into a BOLD, UNPROVEN CAUSAL\n HYPOTHETICAL THEORY.\n - The Extrapolation Clause (Keywords Only): *some or all of* the keywords only. novel idea. \n\n2. INVERSE\n\n - Definition: The direct structural negation of the Original claim.\n - Rule: Directly negate the primary relationship. Do NOT introduce new\n variables. Flip the boolean state of the primary verb (e.g., \"promotes\"\n becomes \"does not promote\").\n\n3. ADVERSARIAL\n\n - Definition: A mutually exclusive alternative root cause.\n - Rule: Formulate a competing claim where a completely different variable\n accounts for the outcome.\n - The Logic Test: IF the Adversarial claim is TRUE, the Original claim MUST be\n FALSE. It must represent a conflict of causality.\n\n4. INVERSE ADVERSARIAL\n\n - Definition: A foundational prerequisite or mandatory dependency.\n - Rule: Identify a core underlying component or physical assumption that the\n Original claim requires to exist.\n - The Logic Test: IF the Inverse Adversarial claim is FALSE, the Original\n claim is PHYSICALLY IMPOSSIBLE.\n\nOUTPUT FORMAT\n\nReturn ONLY valid JSON. Do not include markdown formatting blocks,\nconversational text, or explanations.\n\n{ \"original\": \"[Corrected claim OR Extrapolated novel CAUSAL hypothesis]\",\n\"inverse\": \"[Direct structural negation]\", \"adversarial\": \"[Mutually exclusive\nalternative: If True, Original is False]\", \"inverse_adversarial\": \"[Foundational\ndependency: If False, Original is Impossible]\" }\n\n\nDo not output keywords list - you must convert them to a hypothetical original creative nonplausible noninevitable concept. Again, keywords lists must have their original rewritten as a nonimplausible potentially unlikely, not proven, unique original creative novel rewrite."
},
"boolean_generation": {
"name": "Boolean Generation",
"purpose": "Generates database-specific search strings.",
"when_used": "Stage 1 of each pentamatrix's evaluation loop.",
"content": "You are an expert librarian and systematic reviewer. Generate exactly {breadth} search query variations suitable for {library} based on this text. \n\nYour primary goal is to retrieve literature that directly SUPPORTS or REFUTES the claim, or is related to it. Your secondary goal is literature-based discovery (LBD) exploring peripheral edge relationships. Use OR to discover edges and overlooked abstracts.\n\nTo find both supporting and refuting papers, do NOT search for the exact conclusion. Instead, search for the intersection of the core variables (e.g., Variable A AND Variable B). USE \"OR\" for edge discovery.\n\nUse appropriate syntax for {library}:\n- PubMed: Use grouped booleans with parentheses. Group synonyms using OR (e.g., (\"Term 1\" OR \"Synonym 1\")). Connect distinct core concepts using AND. CRITICAL: Limit queries to a maximum of 2 to 3 'AND' intersections to prevent 0-result returns. Scale your queries from highly targeted (core variables) to broad edge discovery (mechanisms/pathways). Include MeSH terms.\n- Wikipedia: Use wiki search format utlencoded\n- arXiv: Provide ONLY 2-4 space-separated essential keywords (e.g., polar bear, skin, color). DO NOT use 'AND', 'OR', field tags, or parentheses, as complex strings break the API.\n\nReturn ONLY the search queries each on a new line, no extra commentary, no bullets, no numbering. \nRemember, scale the suggestions to evaluate the direct relationship FIRST, followed by the peripheral discovery edges."
},
"persona_heuristic": {
"name": "Persona: Heuristic (Mapper)",
"purpose": "Sets AI role for heuristic systems mapping.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Heuristic).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a heuristic logic mapper and researcher. You play the role of a Systems Architecht.\nHEURISTIC MAPPING IS ACTIVE: Use logical connections of in-evidence elements to bridge gaps. Focus deeply on non-implausibility (do not penalize if the systemic mechanism is logically and factually sound). Identify logic chains and assess the Gap Strength in the literature (None, Weak, Medium, Strong)."
},
"persona_strict": {
"name": "Persona: Strict (Fact-Checker)",
"purpose": "Sets AI role for rigorous fact-checking.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Strict).",
"content": "You are a strict, rigorous scientific fact-checker.\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes."
},
"format_preprint": {
"name": "Format: Preprint",
"purpose": "Defines the academic output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Preprint).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations. You must actually use the quotes you select within the conext of the preprint publication you write."
},
"format_clinical": {
"name": "Format: Clinical",
"purpose": "Defines the medical output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Clinical).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a clinical, medical-professional tone.\nFormat your readable response using these exact clinical headers:\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [CLINICAL BOTTOM-LINE / REWRITTEN CLAIM]\n(Scientific synthesis)\n### [RISK VS REWARD & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [PATIENT APPLICATION: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"format_standard": {
"name": "Format: Standard",
"purpose": "Defines the standard output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Standard).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nIf the user asked a question, you must first provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nThen use a friendly and appropriate tone and answer their intent based solely on the research provided.\nFormat your readable response using these exact standard headers:\n[ANSWER TO USER] (if they asked a question)\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [REWRITTEN CLAIM/PATHWAY]\n(Scientific synthesis based on evidence)\n### [JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [HIGHLIGHTS: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"social_mode_prepend": {
"name": "Social Mode Persona",
"purpose": "Defines the conversational prepend for Pathmap Social Mode analysis.",
"when_used": "When Analysis Mode = 'Pathmap Social' in Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###[FRIENDLY ANSWER TO USER INTENT]\nAddress the user intent directly at the very top. Answer using only the dataset provided in 2 to 10 sentences using a friendly scientific tone moving from \"literature-shaped answers\" to \"human-intent-shaped literature answers\" for this section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"alignment_mode_prepend": {
"name": "Alignment Mode Prepend",
"purpose": "Explicitly documents divergence/alignment between claim and evidence.",
"when_used": "When Analysis Mode = 'Alignment Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes. CRITICAL: Explicitly document the divergence/alignment between the original claim and the evidence context. Note any contradictions or supporting facts clearly."
},
"flexible_mode_eval": {
"name": "Flexible Mode Logic",
"purpose": "Logic used in Flexible Mode",
"when_used": "When Analysis Mode = 'Flexible Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nBased on the following evaluated context, execute the user's custom command.\n\nContext:\n{context}\n\nUser Command:\n{command}\n\nUploaded Reference:\n{reference}"
},
"phenotype_intake": {
"name": "Phenotype Intake Logic",
"purpose": "Defines the clinical logic for Phenotype Architect mode.",
"when_used": "When Analysis Mode = 'Phenotype Architect'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a clinical Phenotype Architect. Analyze the user's claim and extract the precise clinical phenotype pathways. Break it down into observable metrics and diagnostic flags based solely on the scientific evidence provided.\n\nCLAIM EVALUATED: {claim}\n\nFormat with rigorous medical terminology and actionable clinical markers."
},
"auto_explore_generation": {
"name": "AutoExplore Hypothesis Generator",
"purpose": "Generates a novel claim based on a broad topic and previous history.",
"when_used": "Beginning of each loop when AutoExplore is enabled.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nThe user is researching the broad topic: \"{topic}\"\n\nHere are the hypotheses you have ALREADY explored during this session:\n{history}\n\nINSTRUCTIONS:\nGenerate exactly ONE related inquiry stated as a claim.\n- It MUST be formatted as a declarative statement.\n- DO NOT wrap it in quotes.\n- DO NOT include conversational text or explanations.\n- Just return the simple claim."
},
"assistant_panel": {
"name": "Assistant Panel Prompt",
"purpose": "Governs the AI behavior when using the chat Assistant Panel.",
"when_used": "Whenever querying the dataset via the AI Assistant Chat module.",
"content": "You are an expert Data Scientist and Visualization Architect. Answer the user directly and truthfully. Do not introduce yourself.\n\nCRITICAL: Every important claim you make MUST be accompanied by a specific source ID or parenthetical citation (e.g., [ID: 12345]) if it is derived from the context.\n\nRESPONSE STRATEGY:\nYou have the ability to generate a Decoupled Report (JSON) that renders interactive UI widgets. Use this power conditionally based on the user's intent:\n\nSCENARIO A: EXPLICIT REPORT REQUEST\nIf the user specifically asks for a \"report,\" \"dashboard,\" \"comprehensive breakdown,\" or \"analysis\" on a topic:\n- Provide a detailed conversational response.\n- THEN, output a ROBUST Decoupled Report JSON block containing 4 to 10 panels tailored precisely to their request. (Include \"synthesis\" and \"pathmap\" as mandatory selections).\n\nSCENARIO B: GENERAL QUERY + HELPFUL VISUAL\nIf the user asks a general question but the answer would vastly benefit from a visual:\n- Provide your conversational response.\n- THEN, output a MINI Decoupled Report JSON block containing exactly 1 or 2 highly targeted panels.\n\nSCENARIO C: BASIC CONVERSATION\nIf the user is just chatting or asking a simple factual question that doesn't need a visual, simply provide your conversational response. Omit the JSON block entirely.\n\n================================================================\nDECOUPLED REPORT PROTOCOL (JSON)\n================================================================\nDo NOT generate raw HTML, CSS, or JS. Output ONLY valid JSON inside the fencing.\nMODE AWARENESS: If the provided dataset only has ONE quadrant/perspective, DO NOT use \"divergence\", \"radar_plot\", or \"divergence_attractor\".\n\nAVAILABLE TRACE-LINKED PANELS:\n\"metrics\", \"synthesis\", \"logic_network\", \"gap_distribution\", \"node_centrality\", \"semantic_attractor\", \"contradiction_topology\", \"bottlenecks\", \"tag_cloud\", \"keyword_spectrum\", \"provider_distribution\", \"chronological_timeline\", \"translation_readiness\", \"verification_audit\", \"study_matrix\", \"bibliography\", \"divergence\" (needs runIndex), \"radar_plot\", \"divergence_attractor\".\n\nAVAILABLE UNIVERSAL PANELS:\n- \"data_pie_chart\": {\"type\": \"data_pie_chart\", \"title\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"data_bar_chart\": {\"type\": \"data_bar_chart\", \"title\": \"...\", \"xAxisLabel\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"event_timeline\": {\"type\": \"event_timeline\", \"title\": \"...\", \"data\": [{\"date\": \"1990\", \"title\": \"...\", \"desc\": \"...\"}]}\n- \"comparison_matrix\": {\"type\": \"comparison_matrix\", \"title\": \"...\", \"headers\": [\"Name\"], \"rows\": [[\"Item\"]]}\n\nFormat exactly as follows if generating a report:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM ANALYSIS REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"synthesis\", \"title\": \"Main Deliverable Summary\" },\n { \"type\": \"pathmap\", \"title\": \"Global Master Systems Map\" }\n ]\n}\n###REPORT_JSON_END###\n\nCRITICAL RESPONSE SEQUENCE:\n1. First, provide your conversational response.\n2. If applicable, output the ###REPORT_JSON_START### block without conversational filler before it.\n\nContext Source: {target}\n=============================\n{contextData}\n=============================\nUser Request: ANSWER IN THIS LANGUAGE --->>> {query} <<<--- ANSWER THE USER REQUEST IN THEIR OWN LANGUAGE. THE DATASETS CAN BE GENERATED IN ANY LANGUAGE AND MULTIPLE CHAT THREADS MAY EXIST, BUT YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ASKED THE CURRENT QUERY: {query}"
},
"core_evaluation_schema": {
"name": "Core Evaluation Schema (JSON)",
"purpose": "Defines the strict JSON requirements for the final output.",
"when_used": "Appended to every Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42491041\nTitle: Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.\nAbstract: Histone lactylation is an emerging epigenetic modification that covalently links the glycolytic metabolite lactate to histones, thereby establishing a direct link between cellular metabolic status and gene transcription programs. Recent studies have shown that this modification plays a key role in regulating cellular sensitivity to ferroptosis, forming a novel regulatory axis of \"glycolysis-lactylation-ferroptosis.\" This article systematically reviews the biological functions of histone lactylation in the nervous system, with a focus on elucidating how it participates in the pathological processes of various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral stroke, and amyotrophic lateral sclerosis (ALS), by regulating the expression of ferroptosis-related genes. The article integrates the latest research on molecular mechanisms, explores the value of this regulatory axis as a potential biomarker for disease diagnosis and a therapeutic target, and provides an outlook on future research directions in this field.\n\nID: 42459857\nTitle: Experimental evidence of electroacupuncture in ALS mouse models: a systematic review and meta-analysis.\nAbstract: This study aimed to systematically evaluate the therapeutic efficacy of electroacupuncture (EA) in amyotrophic lateral sclerosis (ALS) and to elucidate the underlying neurobiological mechanisms by synthesizing preclinical evidence. According to the PICOS principle, relevant studies were searched in the following databases: PubMed, Web of Science, Embase, Cochrane Library, Scopus, and CNKI. Search terms and strategies were determined based on MeSH terms. The methodological quality of the included studies was assessed using the SYRCLE's Risk of Bias tool and the CAMARADES checklist. Meta-analysis was performed using Stata 15.0 and Rstudio software. Seventeen studies involving 372 animals were included. The quality scores of the included studies ranged from 5 to 8, with an average score of 7. The meta-analysis of the primary outcome, the rotarod test score, showed a significant improvement in the EA group compared to the control group [SMD\u202f=\u202f3.31, 95% CI (2.05, 4.57), Z\u202f=\u202f5.151, p\u202f<\u202f0.001], indicating that EA can enhance motor function in ALS mice. Regarding secondary outcomes, EA intervention alleviated neuroinflammation, promoted neuronal survival, improved axonal regeneration inhibition, and stabilized RNA metabolism homeostasis. Consequently, it slowed disease progression, improved motor performance, prolonged survival time, and effectively protected motor neurons at the histopathological level (p\u202f<\u202f0.05). These findings underscore the potential of EA as a promising multimodal therapeutic strategy for ALS. For the heterogeneity observed in the rotarod test, sensitivity analysis, subgroup analysis, and meta-regression did not identify its source. However, potential publication bias was detected, which might contribute to the heterogeneity. The heterogeneity for other outcome measures might originate from differences in stimulation parameters (e.g., waveform), acupoint selection, or treatment duration. This meta-analysis demonstrates that EA confers significant neuroprotective benefits in preclinical ALS models, primarily through multi-target modulation of key pathological processes such as neuroinflammation, aberrant cell death signaling, and RNA metabolism. These preclinical findings underscore the potential of electroacupuncture as a complementary neuroprotective strategy and warrant further investigation in rigorous clinical trials. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251229183.\n\nID: 42431556\nTitle: Fisetin prevents deterioration of cellular functions in amyotrophic lateral sclerosis variants G262R and P438L of SQSTM1 in SH-SY5Y cells.\nAbstract: Oxidative stress is widely accepted as one of the important factors contributing to neurodegeneration, leading to fatal neurodegenerative diseases (NDD) such as Amyotrophic Lateral Sclerosis. Since flavonoids possess antioxidant properties, we investigated whether Fisetin (FS) and Quercetin (QR) protected cells from oxidative stress arising from pathogenic mutations G262R (G\u00a0>\u00a0A) and P438L (C\u00a0>\u00a0T) of SQSTM1 found in Indian ALS patients. SQSTM1 codes for p62 protein and is involved in multiple signaling pathways through its various domains. We studied changes in cell viability and cellular functions using immunoblotting, confocal microscopy, immunoprecipitation and FACS analysis in the presence and absence of FS and QR. Supplementation with FS and QR in SH-SY5Y cells expressing SQS-wild type and mutants increased cell viability and decreased ROS formation. Also, Nrf2 protein levels increased to offset oxidative stress response. In addition, we studied the effect of FS on the nuclear-cytoplasmic distribution of TDP-43 protein, which serves as a hallmark for ALS. FS corrected the nuclear-cytoplasm translocation of TDP-43 protein and decreased late apoptosis in mutants. Our study illustrates that both FS and QR shield cells from oxidative stress, and that FS imparted better protection against the pathogenic effect of SQSTM1 mutants in SH-SY5Y neuronal cells.\n\nID: 42419281\nTitle: Sealing and healing: A two-step model for plasma membrane repair.\nAbstract: Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.\n\nID: 42400730\nTitle: Neuroprotective potential of resveratrol in Parkinson, Huntington, amyotrophic lateral sclerosis, and multiple sclerosis: a comprehensive review.\nAbstract: Resveratrol shows neuroprotective effects in preclinical studies across a number of neurodegenerative illnesses, including Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's disease (HD), and it enhances mitochondrial function through stimulation of the AMPK/SIRT1/PGC-1\u03b1 pathway, thereby improving mitochondrial oxidative capacity and ATP generation. The natural polyphenol lowers \u03b1-synuclein accumulation and affects autophagy; both markers of PD. Combining nano\u2011resveratrol formulations with L\u2011DOPA has shown greater therapeutic efficacy in animal models (MPTP mouse), while co\u2011administration with EGCG has shown synergistic neuroprotection in vitro (SH\u2011SY5Y cells). These combination strategies offer potential advantages in neuroprotection and symptom alleviation while minimizing adverse drug effects. Resveratrol activates SIRT1 and AMPK signaling in preclinical models, enhancing mitochondrial biogenesis, lowering apoptosis, and restoring cellular resilience. The effectiveness of various models and dosages varies. The primary mechanism by which resveratrol promotes neuronal survival and remyelination in multiple sclerosis is through SIRT1 activation, which does not directly reduce inflammation. As innovative delivery systems, intranasal nanoparticles and exosomes produced from macrophages have shown improved CNS targeting accuracy. Resveratrol slows down neurodegeneration and improves the prognosis of HD by improving motor function and stimulating mitochondrial biogenesis in addition to activating neuroprotective ERK signaling. All of these results point to resveratrol's several pathways as a strong contender for neurodegenerative disease adjunctive treatment. The current evidence base is insufficient to support clinical use of resveratrol for any of the four diseases. Further rigorous preclinical studies (including TDP-43 models for ALS, SIRT1 knockout studies, and human-feasible dosing) and well-designed clinical trials with pharmacokinetic endpoints are required before any clinical recommendations can be made.\n\nID: 42389275\nTitle: Role of gut microbiota in melanosis coli: from anthraquinone biotransformation to mucosal homeostasis dysbiosis.\nAbstract: Melanosis coli (MC) is a benign and usually reversible condition characterized by brownish-black pigmentation of the colonic mucosa and is commonly associated with chronic exposure to anthraquinone laxatives (ALs). The best-established histopathological sequence involves AL-related epithelial apoptosis, phagocytosis of apoptotic bodies by macrophages, and subsequent lipofuscin deposition. Emerging evidence suggests that the gut microbiota (GM) may contribute to this process by converting pharmacologically inactive anthraquinone glycosides into active anthrone metabolites, including rhein anthrone. This narrative review summarizes available MC-specific findings and clearly distinguishes them from mechanistic hypotheses extrapolated from constipation, intestinal barrier, and microbiome literature. We discuss microbial \u03b2-glucosidases and reductases involved in AL biotransformation, reported changes in microbial diversity and SCFA-producing taxa in MC or constipation-associated cohorts, and plausible links with barrier dysfunction, bile-acid metabolism, tryptophan-derived metabolites, and LPS-TLR4 signaling. We therefore present the \"Microbiota-Apoptosis Axis\" as a proposed framework rather than a validated causal pathway. Finally, we review GM-targeted strategies, including probiotics, synbiotics, and fecal microbiota transplantation, while emphasizing that direct clinical evidence in MC remains limited and that cessation of anthraquinone laxatives remains the primary management strategy.\n\nID: 42351313\nTitle: A rare missense variant impacting NEK1 kinase function is associated with ALS.\nAbstract: Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.\n\nID: 42350373\nTitle: Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.\nAbstract: Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.\n\nID: 42343570\nTitle: STMN2 protein depletion via translation deficits and stress granules in amyotrophic lateral sclerosis.\nAbstract: STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, in situ single-molecule analysis of translation and RNA localisation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion under stress. We find that human STMN2 protein level is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translation repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. We find that low pre-stress STMN2 sensitises neuronal cells to stress-induced apoptosis, whereas moderately increased STMN2 is protective under stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS (ALS-FUS) models, which may compensate for translation/stress granule defects in this disease subtype. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common denominators in neurodegeneration - dysregulation of translation and stress granules - in STMN2 depletion, independent of TDP-43 loss of function. It also describes an RNA-based compensatory mechanism in ALS underling the unique vulnerability of neurons with developing TDP-43 pathology.\n\nID: 42335888\nTitle: An emergent disease-associated motor neuron state precedes cell death in ALS.\nAbstract: To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named \"disease-associated motor neurons\" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.\n\nID: 42332177\nTitle: Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.\nAbstract: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.\n\nID: 42310292\nTitle: Impact of BECLIN1 haploinsufficiency on goblet cell function and susceptibility to colitis.\nAbstract: BECLIN1 is a central regulator of autophagy and endocytic trafficking essential for epithelial homoeostasis. While complete intestinal epithelial loss of BECLIN1 causes fatal enteritis originating in the small intestine, the consequences of its partial loss in the gut remain unclear. Given that BECLIN1 expression can vary in human disease, we investigated whether reduced BECLIN1 is sufficient to impair gut barrier function. Heterozygous Becn1 deletion (Becn1IEC+/-) in the mouse intestinal epithelium caused subtle but significant defects. These included shortened small intestines and altered epithelial architecture, despite preservation of basal autophagy, implicating trafficking-related functions. Supporting this conclusion, Becn1IEC+/- small intestinal epithelial cells showed modest increases in RAB5+ve vesicles, redistribution of E-CADHERIN and F-actin along lateral membranes and altered apico-basal cell morphology. Given the absence of overt small intestinal epithelial disruption or inflammation, as seen with complete loss of BECLIN1, we next addressed whether BECLIN1 insufficiency manifests a phenotype under stress or in other gut regions. Indeed, in the colon, Becn1IEC+/- mice exhibited reduced colonic crypt length, baseline goblet cell loss and reduced mucin production, particularly in mature goblet cells, indicating vulnerability of the mucus barrier. When challenged with dextran sulfate sodium (DSS), Becn1IEC+/- mice exhibited greater weight loss, higher disease activity, more severe histological colitis, and disproportionate loss of neutral mucins, with inflammation confined to the mucosa. Together, these findings show that BECLIN1 insufficiency does not trigger spontaneous inflammation but destabilises epithelial organisation and barrier defence, thereby sensitising the gut to inflammatory challenge and further positioning BECLIN1 as a threshold-dependent determinant of intestinal resilience.\n\nID: 42304926\nTitle: Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.\nAbstract: Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-\u03b2 deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and m\u00fcller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.\n\nID: 42274592\nTitle: The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword.\nAbstract: Iron is an essential micronutrient that plays a central role in numerous biological processes. Despite its relatively low abundance in the human body, iron is particularly critical for brain function. Systemic and cerebral iron homeostasis is tightly regulated through coordinated mechanisms involving absorption, transport, storage, and recycling. Within the brain, iron metabolism is further controlled by the blood-brain barrier and specialized neural cell populations, including neurons, astrocytes, oligodendrocytes, and microglia. Iron is indispensable for neurodevelopment, supporting neurogenesis, myelination, and neurotransmitter synthesis. However, both iron deficiency and iron overload have detrimental consequences. Early-life iron deficiency disrupts neural development and leads to long-lasting cognitive, motor, and behavioral impairments, whereas excessive iron accumulation promotes oxidative stress, ferroptosis, and neuroinflammation. These mechanisms have been described to contribute to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation, and amyotrophic lateral sclerosis. This review first outlines systemic and brain iron metabolism, highlighting how neural cells regulate homeostasis. Next, it examines iron's physiological roles, particularly in neurogenesis and neurodevelopment. Finally, it explores iron's involvement in neurodegenerative diseases, emphasizing neuroinflammation as a primary mechanism of iron toxicity.\n\nID: 42274555\nTitle: Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks.\nAbstract: Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial-ROS-inflammatory signaling, aggregation-proteostasis failure, synaptic-neuroimmune dysfunction, and gut-brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways-play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood-brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles.\n\nID: 42261159\nTitle: The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?\nAbstract: The review specifically examines the pivotal role of HDAC6 in the pathophysiological pathway of Amyotrophic Lateral Sclerosis (ALS), an escalating neurodegenerative ailment marked by the discerning damage to motor neurons. Several lines of evidence implicate inadequate proteostasis in significantly influencing neuronal degeneration. The accumulation of misfolded proteins and proteotoxicity are highlighted as significant factors in ALS pathophysiology. Key pathological hallmarks include ubiquitin-positive inclusions, disrupted RNA metabolism, cytoskeletal perturbations, and compromised axonal transport systems. HDAC6 dysregulation disrupts axonal transport, impairing mitochondrial function and increasing oxidative stress, leading to rapid motor neuron damage and cell death. The enzyme's aberrant deacetylation of \u03b1-tubulin destabilizes microtubules and impairs intracellular trafficking. Despite HDAC6's participation in these unfavorable processes, it also exerts neuroprotective properties. It deacetylates tubulin, promoting efficient axonal transport and autophagic clearance. HDAC6 helps form aggresomes and stress granules, which are essential for cellular defence against proteotoxic stress. Through its zinc finger ubiquitin-binding domain, HDAC6 interacts with polyubiquitinated proteins, facilitating their autophagic degradation. HDAC6 inhibition can boost autophagic flux and reduce protein aggregation, while its activation may amplify the protective effects. This dichotomous behaviour of HDAC6 may pose an obstacle to the design of targeted therapy. Illuminating the complex mechanisms through which HDAC6 influences neurodegeneration and neuroprotection is important before constructing effective treatments for ALS. The review provides a clear understanding of the complex role of HDAC6 in ALS pathogenesis and highlights potential strategies to improve the prognosis of people affected by this neurological illness.\n\nID: 42259394\nTitle: Natural monomer compounds in neurodegenerative diseases: Targeting ferroptosis and neuroinflammation.\nAbstract: Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss driven by oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Ferroptosis, an iron-dependent and lipid peroxidation-associated form of regulated cell death, has recently been identified as a key contributor to neuronal vulnerability. Emerging evidence demonstrates that purified natural monomer compounds derived from medicinal plants exert potent neuroprotective effects by targeting ferroptosis and neuroinflammatory pathways. Representative agents such as curcumin, baicalin, resveratrol, and ginsenoside Rg1 activate nuclear factor E2-related factor-2 and glutathione peroxidase 4 signaling to preserve redox balance, while suppressing microglia-mediated inflammation through inhibition of toll-like receptor 4 pathways. This review highlights the interplay between ferroptosis and neuroinflammation in NDDs, summarizes the regulatory effects of bioactive herbal monomer compounds, and discusses recent advances in multi-omics profiling, nano-delivery strategies, and translational research. By modulating the ferroptosis-neuroinflammation axis, these compounds may represent promising therapeutic candidates for NDDs.\n\nID: 42246025\nTitle: Editorial: Regulated cell death and neurological diseases.\nAbstract: \n\nID: 42243993\nTitle: Hyperoside protects against poly-GR-mediated neurodegeneration via regulation of mitochondrial fission and oxidative stress in C9orf72-associated ALS.\nAbstract: Arginine-rich poly-glycine-arginine (poly-GR), a toxic dipeptide repeat protein generated from C9orf72 hexanucleotide repeat expansion, drives mitochondrial dysfunction, oxidative stress, and neuronal loss in amyotrophic lateral sclerosis (ALS). Hyperoside, a bioactive flavonoid, exhibits antioxidant and cytoprotective properties, but its therapeutic relevance to C9orf72-associated ALS remains unclear. To determine whether hyperoside attenuates poly-GR-induced mitochondrial and oxidative injury and improves neuronal survival in cellular and animal models of C9orf72-ALS. A combined in vitro and in vivo experimental study using motor neuron-like cells and an AAV-mediated neonatal mouse model of poly-GR toxicity. NSC34 cells expressing EGFP-GR50 were analyzed for mitochondrial morphology, membrane potential, ROS generation, antioxidant signaling, and apoptosis using confocal microscopy, CellROX/MitoTracker assays, Western blot analysis, and viability testing. For in vivo assessment, neonatal mice received intracerebroventricular AAV9-EGFP-GR50 followed by intraperitoneal hyperoside (10\u00a0mg/kg). Survival, cerebral hemisphere length, and cortical NeuN\u207a neuron numbers were quantified. Poly-GR expression induced pronounced mitochondrial fragmentation, reduced membrane potential, elevated ROS, and suppressed Nrf2/HO-1/GPx4 signaling, accompanied by increased Drp1 and reduced Opa1 expression. Hyperoside reversed these abnormalities by restoring mitochondrial integrity, normalizing the Drp1/Opa1 balance, enhancing Nrf2 nuclear accumulation, and increasing the expression of HO-1 and GPx4. Hyperoside also reduced cleaved caspase-3 and corrected the Bax/Bcl-2 ratio, improving cell viability under basal and oxidative stress conditions. In vivo, hyperoside modestly prolonged survival, increased cerebral hemisphere length, and significantly preserved cortical neuronal numbers in AAV9-EGFP-GR50 mice. Hyperoside mitigates poly-GR-induced neurotoxicity by alleviating excessive mitochondrial fission, strengthening Nrf2-dependent antioxidant defenses, and suppressing apoptosis. These findings support hyperoside as a promising multi-target therapeutic candidate for C9orf72-associated ALS.\n\nID: 42242586\nTitle: Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.\nAbstract: Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits FIG4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.\n\nID: 42227472\nTitle: Fisetin and Neurodegeneration: From Preclinical Studies to Potential Clinical Applications.\nAbstract: Neurodegenerative diseases (NDs), like Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, pose significant challenges due to their gradual deterioration and limited available treatments. Fisetin, a naturally occurring flavonoid, has gained attention for its neuroprotective properties. This review explores the therapeutic potential of fisetin in NDs, focusing on its molecular processes and signaling pathways. Additionally, fisetin exhibits significant protective properties, particularly in reducing oxidative stress, neuroinflammation, and apoptosis. It enhances neuronal survival and reduces neuroinflammation by regulating key pathways, such as Nrf2/ARE, PI3K/Akt, and NF-\u03baB. It also has anti-inflammatory, anti-apoptotic, and antioxidant actions. It stimulates autophagic processes, aiding in the removal of harmful protein aggregates, like tau tangles and amyloid plaques, which are hallmarks of NDs. Fisetin, as demonstrated through behavioral evaluations in animal models, has been found to improve motor coordination, synaptic plasticity, and cognitive function. Furthermore, fisetin's potential as a neuroprotective drug is emphasized by its role in enhancing autophagy and reducing tau and amyloid pathology. Research has shown its efficacy in enhancing neural resilience, synaptic plasticity, and cognitive function in both preclinical and in vitro settings. However, clinical translation remains limited due to challenges in pharmacokinetics and bioavailability, despite robust experimental evidence. Further clinical trials are needed to evaluate the safety and efficacy of fisetin, especially in early-stage NDs, explore potential synergistic effects, and understand the molecular interactions. The review demonstrates fisetin's therapeutic potential, recent research, and future strategies for NDs, highlighting bioavailability limitations and the need for new formulations or delivery systems.\n\nID: 42212756\nTitle: 5-Hydroxytryptamine Distribution Alteration in Both Neuron and Synapse of Tg(SOD1*G93A)1gur Mice: A Potential Intervention Candidate Strategy for Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; the precise pathogenesis of sporadic ALS (sALS) has not yet been elucidated up to now. Previous studies revealed that the abnormal alterations of some non-motor neurons (non-MN) were a potential pathogenesis of sALS. Therefore, this study aims to search the potential evidences of non-MN in the pathogenesis of ALS via exploring potential relationships between 5-hydroxytryptamine (5-HT) neurons and the development of ALS. We employed fluorescent immunohistochemistry to investigate the altered distribution patterns of 5-HT and tryptophan hydroxylase 2 in the spinal cord and brainstem of Tg(SOD1*G93A)1Gur (TG) and wild-type (WT) mice. Additionally, we used western blot to analyze the expression levels of 5-hydroxytryptamine receptor 1A (5-HTR1A) and 5-HTR2A. Our findings revealed that 5-HT synapses were primarily distributed in the funiculus lateralis, anterior horn, posterior horn, central lateral column, and the area around the central canal of cervical, thoracic, and lumbar segments, and raphe nucleus as well as lateral paragigantocellular nucleus, and gradually reduced following age increase in WT mice. However, 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem gradually increased following the progression of disease and presented a significantly negative correlation between the increased distribution of 5-HT synapses and neurons and the reduction of neural cell number (positively correlated with the increase in neural cell death) at the onset and/or progression stage of TG mice. 5-HTR1A significantly increased, while 5-HTR2A significantly decreased at the onset stage of TG mice. Our study speculated that the distribution changes of 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem play a potential protective role in the pathogenesis of sALS through a compensatory 5-HT increase.\n\nID: 42204151\nTitle: Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.\nAbstract: TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.\n\nID: 42182325\nTitle: C9orf72 -associated G4C2 hexanucleotide repeat expression in Drosophila mushroom bodies causes age dependent TDP-43 pathology and dementia relevant phenotypes mediated in part by the glypican Dlp/GPC6.\nAbstract: Hexanucleotide repeat expansions (HREs) in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the age-, sex-, repeat-length-, and circuit-specific influence on the pathology of neurons remains incompletely understood. Here, we established a Drosophila model of C9orf72 -associated dementia by expressing G4C2 repeats in mushroom body neurons (MBNs), a brain region critical for memory, locomotion, and sleep. Expression of 44X G4C2 repeats ((G4C2) 44X ) led to progressive axonal thinning, age-dependent accumulation of Repeat Associated Non-AUG (RAN) translated GR-GFP dipeptide repeat (DPR) puncta, premature nuclear-to-cytoplasmic mislocalization of endogenous TDP-43, increased caspase, reduced lifespan and a loss of presynaptic active zones. Behaviorally, (G4C2) 44X expression caused locomotor hyperactivity, altered spatial working memory, and fragmentation of sleep architecture in an age- and sex-dependent manner, recapitulating core features of FTD. Surprisingly, the shorter (G4C2) 12X repeat, traditionally considered a control, also produced detectable RAN translation and intermediate phenotypes in aging MBNs, suggesting that length- and tissue-associated factors modulate repeat toxicity. We further identified a repeat-length- and age-dependent reduction of the glypican Dally-like protein (Dlp) in (G4C2) 44X consistent with disrupted Wnt-related signaling linked to TDP-43 proteinopathies. Restoring Dlp expression in MBNs mitigated locomotor and working-memory alterations, and loss of presynaptic active zones. In contrast, axonal degeneration, TDP-43 mislocalization, and lifespan were not significantly improved by restoring Dlp, suggesting that multiple mechanisms contribute to G4C2-induced toxicity. Supporting our findings in Drosophila MBNs, a CRISPRi screen in TDP-43 knock-down iNeurons identified GPC6, a human ortholog of Dlp, as a significant contributor to TDP-43 dependent synaptic loss. Together, our findings reveal an aging-sensitive, circuit-specific model of C9orf72 -associated neurodegeneration and highlight roles for DPR accumulation and Dlp/GPC6 dependent synaptic loss in FTD pathomechanisms.\n\nID: 42180530\nTitle: Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.\nAbstract: Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.\n\nID: 42178983\nTitle: Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.\nAbstract: Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.\n\nID: 42171198\nTitle: Targeting lipid nanoparticle mediated co-delivery of edaravone and kaempferol for amyotrophic lateral sclerosis therapy.\nAbstract: Amyotrophic lateral sclerosis (ALS) is characterized by a progressive and selective loss of motor neurons in the central nervous system, particularly in the brain and spinal cord. However, the main cellular mechanisms and cell death pathways leading to motor neuron degeneration have not yet been clarified. Research indicates evidence of ferroptosis in ALS, and the natural compound kaempferol has been demonstrated to inhibit neuronal ferroptosis. However, damage to the blood-brain barrier (BBB) prevents the drug from penetrating the central nervous system, which significantly reduces its therapeutic efficacy. Here, we developed a targeted delivery system named Eda/Kae@Lip-RGD (EKLR), which consisted of liposome-grafted RGD peptides for the co-delivery of the drugs kaempferol and edaravone, capable of crossing the BBB to provide co-delivery of kaempferol and edaravone for combined treatment of ALS. As expected, treatment with EKLR for one month significantly slowed down weight loss and improved athletic performance in SOD1G93A transgenic mice. Mechanistically, this nanomedicine suppressed ferroptosis by upregulating the antioxidant proteins GPX4 and SLC7A11, alongside the downregulation of Nrf2 and ACSL4 levels, thus collectively preserving neuronal integrity. Meanwhile, EKLR restored the normal morphology and the survival rate of neurons and maintained the mitochondrial structure and morphological integrity. Accordingly, this nanoplatform may represent a distinctive and potentially effective strategy for achieving neuroprotection in ALS as well as in other disorders of the central nervous system.\n\nID: 42156174\nTitle: COMMD1 Induces Copper Deficiency of SOD1 by Inhibiting the Palmitoylation of CCS in ALS.\nAbstract: Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia-inducible factor 1 subunit alpha (HIF-1\u03b1)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1G93A transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.\n\nID: 42153537\nTitle: MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.\nAbstract: Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the MT-RNR1/12S rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-\u03baB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, in vivo overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery.Abbreviations: AA\u2009=\u2009arachidonic acid, AAV\u2009=\u2009adeno-associated virus, ACTA2/\u03b1-SMA\u2009=\u2009actin alpha 2, smooth muscle, aorta, ALs\u2009=\u2009autolysosomes, BECN1\u2009=\u2009beclin 1, CASP1\u2009=\u2009caspase 1, CQ\u2009=\u2009chloroquine, CTSB\u2009=\u2009cathepsin B, CTSD\u2009=\u2009cathepsin D, CTSL\u2009=\u2009cathepsin L, Co-IP\u2009=\u2009co-immunoprecipitation, DEGs\u2009=\u2009differentially expressed genes, ELISA\u2009=\u2009enzyme-linked immunosorbent assay, F-CHP\u2009=\u20095-FAM-conjugated collagen hybridizing peptide staining, GSDMD\u2009=\u2009gasdermin D, GO\u2009=\u2009gene Ontology, GPT/ALT\u2009=\u2009glutamic pyruvic transaminase, soluble, GOT1/AST\u2009=\u2009glutamic-oxaloacetic transaminase 1, soluble, HE\u2009=\u2009hematoxylin-eosin, HUVECs\u2009=\u2009human umbilical vein endothelial cells, IP/MS\u2009=\u2009immunoprecipitation coupled with mass spectrometry, IL1B/IL-1\u03b2\u2009=\u2009interleukin 1 beta, IL18\u2009=\u2009interleukin 18, IP\u2009=\u2009intraperitoneal injection, IV\u2009=\u2009intravenous injection, LDBF\u2009=\u2009laser Doppler blood flow, LMP\u2009=\u2009lysosomal membrane permeability, MAP1LC3/LC3\u2009=\u2009microtubule-associated protein 1 light chain 3, MAPK\u2009=\u2009mitogen-activated protein kinase, NAGLU\u2009=\u2009alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-\u03baB\u2009=\u2009nuclear factor kappa B, NLRP1\u2009=\u2009NLR family pyrin domain containing 1, NLRP3\u2009=\u2009NLR family pyrin domain containing 3, PECAM1/CD31\u2009=\u2009platelet/endothelial cell adhesion molecule 1, PLA2G4A/cPLA2\u2009=\u2009phospholipase A2, group IVA (cytosolic, calcium-dependent), PYCARD/ASC\u2009=\u2009PYD and CARD domain containing, PIK3C3/VPS34\u2009=\u2009phosphatidylinositol 3-kinase catalytic subunit type 3, PMA\u2009=\u2009phorbol 12-myristate 13-acetate, ROS\u2009=\u2009reactive oxygen speciesSQSTM1/p62\u2009=\u2009sequestosome 1, SPR\u2009=\u2009surface plasmon resonance, scRNA-seq\u2009=\u2009single-cell RNA sequencing, UMAP\u2009=\u2009uniform manifold approximation and projection, WB\u2009=\u2009western blotting.\n\nID: 42148083\nTitle: Ferroptosis-immune crosstalk in CNS diseases: mechanisms and translational insights.\nAbstract: Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, which plays a pivotal role in regulating the inflammatory-immune microenvironment of central nervous system (CNS) diseases. Mounting evidence indicates that dysregulated iron metabolism and an imbalance in antioxidant defenses can induce ferroptosis in neurons and glial cells while simultaneously remodeling immune cell function, thereby establishing a bidirectional feedback loop that amplifies neuroinflammation and tissue damage. In neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), pro-inflammatory cytokines such as TNF-\u03b1 and IL-1\u03b2 released by activated microglia upregulate neuronal iron transporters (e.g., DMT1 and TfR1), promoting iron accumulation and ferroptotic cell death. In turn, damage-associated molecular patterns released from ferroptotic cells further potentiate immune activation, forming a self-amplifying cycle. In contrast, within the glioma microenvironment, CD8+ T cell-derived IFN-\u03b3 suppresses SLC7A11 expression in tumor cells, leading to glutathione depletion and glutathione peroxidase 4 inactivation, thereby triggering ferroptosis and modulating anti-tumor immunity. Although targeting ferroptosis or neuroimmune pathways has shown therapeutic promise in mitigating neurological deficits and enhancing anti-tumor responses, the underlying mechanisms governing ferroptosis-immune crosstalk remain inadequately characterized. Herein, this review systematically summarizes the key biological characteristics of ferroptosis and immune responses, with particular emphasis on their interplay across major CNS disorders (i.e., AD, PD, ALS, multiple sclerosis, stroke, and glioma). Furthermore, we discuss emerging therapeutic strategies encompassing small molecules, immunomodulatory approaches, and nanotechnology-based interventions, highlighting the ferroptosis-immune axis as a promising therapeutic target for CNS diseases.\n\nID: 42143042\nTitle: VCP modulation ameliorates pathological features in C9orf72 models.\nAbstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.\n\nID: 42136278\nTitle: Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.\nAbstract: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification. A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs. ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-\u03baB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies. Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers. Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.\n\nID: 42129145\nTitle: A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.\nAbstract: RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.\n\nID: 42484672\nTitle: Protein arginine methyltransferases as regulators of phase separation: implications in cancer and neurodegenerative diseases.\nAbstract: Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, a key post-translational modification (PTM) regulating chromatin organization, RNA metabolism, and signaling. Recent studies reveal that PRMT-mediated methylation also modulates liquid-liquid phase separation (LLPS), which organizes membraneless condensates controlling transcription, stress response, and genome stability. Dysregulated PRMT activity disrupts condensate dynamics, contributing to cancer and neurodegenerative diseases. In cancer, PRMT1, PRMT5, and PRMT6 promote tumor progression via methylation-dependent condensates that enhance oncogenic transcription and stress resistance. In the nervous system, PRMT1, PRMT4, PRMT5, PRMT6, and PRMT8 regulate LLPS of proteins, linking aberrant methylation to ALS and Huntington's disease. This review highlights PRMTs as key modulators of phase separation and potential therapeutic targets in both oncology and neurodegeneration.\n\nID: 42468211\nTitle: FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss and declining motor function; however, effective therapies remain limited. To support unbiased therapeutic discovery, we aimed to develop a high-throughput phenotypic screening platform based on a transgenic zebrafish model expressing the human ALS-associated FUS-R521C mutant (mtFUS). This model was generated using a modified QF-based binary expression system and exhibited early-onset pathological features, including elevated oxidative stress, progressive neuronal degeneration, and impaired locomotor activity, thereby recapitulating the key aspects of FUS-associated ALS. Transcriptomic profiling revealed molecular signatures resembling those reported in patient-derived motor neurons, including dysregulated neuroactive ligand-receptor signaling, immune activation, and stress-response pathway alterations. Using this platform, we identified tribenzylamine (TBA) as a candidate compound that improves locomotor performance and significantly reduces reactive oxygen species levels. Integrated transcriptomic and biochemical analyses suggested that TBA induces coordinated molecular changes, including normalization of neuronal activity-related gene expression, modulation of immune and metabolic pathways, and restoration of hormone-related signaling. TBA reversed FUS-induced reductions in key neuronally active sex steroids, including estrogen and progesterone, and increased estrogen-responsive gene expression, suggesting a partial recovery of neuronally active sex steroid homeostasis. These findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify TBA as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.\n\nID: 42451691\nTitle: Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.\nAbstract: Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.\n\nID: 42426573\nTitle: TSR and peroxidase genes confer resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl in Alopecurus aequalis.\nAbstract: Alopecurus aequalis poses severe threat to global wheat production due to evolving resistance to acetyl-CoA carboxylase (ACCase)- and acetolactate synthase (ALS)-inhibiting herbicides. In this study, the resistance mechanisms of a field-evolved resistant population (R) were systematically investigated using dose-response bioassays, target-site gene sequencing, inhibitor assays, antioxidant enzyme activity measurements, RNA sequencing (RNA-seq), quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and yeast functional validation. Dose-response results revealed that the R population exhibited moderate resistance to fenoxaprop-P-ethyl (RI\u2009=\u20099.58) and low-level resistance to mesosulfuron-methyl (RI\u2009=\u20093.07). Cross-resistance testing indicated that the R population was resistant to other ACCase-inhibiting herbicides (haloxyfop-P-methyl, clodinafop-propargyl, clethodim, and pinoxaden) and the ALS-inhibiting herbicide rimsulfuron. Target-site sequence analysis identified two mutations in the R population: Ile-1781-Leu (ACCase) and Pro-197-Ser (ALS1). Pretreatment with the cytochrome P450 and GST inhibitor did not reverse resistance to fenoxaprop-P-ethyl or mesosulfuron-methyl. Compared to the susceptible (S) population, the R population had significantly lower H2O2 content and higher activities of peroxidase (POD) and catalase (CAT), indicating an enhanced reactive oxygen species (ROS) scavenging capacity. RNA-seq and qRT-PCR analyses identified three POD-annotated contigs (PODSPC4, POD12-1, POD12-2) that were upregulated in the R population. Yeast heterologous expression validated that AaPOD12-1 and AaPOD12-2 significantly increased yeast resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl. These results demonstrate that resistance in the R population is co-mediated by target-site mutations and non-target-site resistance involving enhanced ROS scavenging, with AaPOD12-1 and AaPOD12-2 representing the first functionally characterized antioxidant enzyme genes associated with herbicide resistance in A. aequalis. \u00a9 2026 Society of Chemical Industry.\n\nID: 42425084\nTitle: RNA-dependent SFPQ condensates coordinate multidimensional regulation of extra-long neuronal genes.\nAbstract: The mammalian brain uniquely expresses a large repertoire of extra-long genes critical for neuronal development and function, yet these transcripts are particularly vulnerable to dysregulation linked to neurological disorders, such as autism spectrum disorder and amyotrophic lateral sclerosis. The molecular mechanisms that ensure their stable expression remain poorly understood. Here, we show that the RNA-binding protein SFPQ forms meshwork-like biomolecular condensates that scaffold a multidimensional gene regulatory complex essential for long-gene expression. Super-resolution microscopy and functional perturbation assays demonstrate that disruption of SFPQ condensates impairs both extra-long gene expression and splicing. Proximity-dependent biotin labeling combined with mass spectrometry (BioID-MS) reveals that SFPQ condensates recruit transcriptional elongation factors, splicing regulators, and chromatin remodelers. Notably, many of these interactors overlap with autism-associated genes, suggesting direct disease relevance. These findings define a higher-order nuclear architecture organized by SFPQ and provide mechanistic insight into long-gene transcriptopathies underlying neurological disorders.\n\nID: 42419740\nTitle: TOP1MT rs2293925 is an enhancer-active regulatory SNP that shapes mitochondrial R-loop dynamics.\nAbstract: Mitochondrial topoisomerase 1 (TOP1MT) regulates mitochondrial DNA (mtDNA) topology during transcription and replication. Perturbed mtDNA maintenance and RNA metabolism have been implicated in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Here we show that the common TOP1MT variant rs2293925 (R525W) has enhancer-like activity and is associated with increased mitochondrial R-loops (RNA\u2009:\u2009DNA hybrids). Tissue-dependent expression, quantitative trait locus analysis, chromatin-state annotation, reporter assays, and allele-specific DNA-protein binding assays support a transcriptional regulatory role for rs2293925. In isogenic cell models, rs2293925 increased TOP1MT mRNA and protein abundance, and this was accompanied by increased mitochondrial R-loop signal. TOP1MT trapping with lamellarin D supported increased TOP1MT-R525W occupancy at mitochondrial control region sites together with enhanced R-loops, consistent with altered TOP1MT-mtDNA interaction and/or increased TOP1MT abundance. Elevated mitochondrial R-loop signal was also detected in a pilot cohort of sporadic ALS samples carrying rs2293925 and in neural stem cells derived from C9orf72-positive ALS patients. These data support a dual-effect model in which rs2293925 increases TOP1MT expression and is associated with altered mitochondrial R-loop dynamics, linking common genetic variation to mitochondrial nucleic acid stress in disease-relevant contexts.\n\nID: 42398690\nTitle: Mutant superoxide dismutase 1-catalyzed hydrogen therapy for amyotrophic lateral sclerosis achieved by intercepting oxidative stress-neuroinflammation crosstalk.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord, with mutant superoxide dismutase 1 (SOD1) induced oxidative stress and neuroinflammation as key pathogenic drivers. Here, we uncover that mutant SOD1 is both a Fenton-like agent able for catalytical generation of \u00b7OH and a hydrogenation catalyst for H2 scavenging reactive oxygen species. To enhance the bioavailability of H2, we develop an orally administered Mg2Si nanosheets based feed for sustained release of high-amount H2. On an ALS model of hSOD1G93A transgenic mice, Mg2Si feed remarkably delays ALS progression, improves the motor performance of ALS mice, and extends their lifespan. Histopathologically, oral Mg2Si treatment ameliorates motor neuron degeneration, misfolded SOD1 aggregation and reactive gliosis in spinal cord, while protecting neuromuscular junctions and ameliorating muscle atrophy during disease progression. Transcriptomic analysis demonstrates the H2-mediated down-regulation of both oxidative stress and neuroinflammatory pathways in response to the suppression of NLRP3 inflammasome activation. The proposed strategy of catalyzed hydrogen therapy offers an inspiration for metalloproteases-related neurodegenerative diseases treatment. STATEMENT OF SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is an incurable and devastating neurodegenerative disease lacking effective clinical interventions. Although hydrogen gas (H2) exhibits promising neuroprotective potential, conventional H2 therapy is severely limited by unstable and transient H2 release, failing to sustain long-term treatment requirements for chronic ALS pathogenesis. To overcome this bottleneck, we engineer oral administrable Mg2Si nanosheets that enable sustained H2 release via gastrointestinal retention, achieving stable long-term hydrogen supplementation in vivo. Mechanistically, Mg2Si-derived H2 efficiently eliminates excess free radicals triggered by toxic mutant SOD1, and further disrupts the pathological crosstalk between oxidative stress and neuroinflammation in ALS. In transgenic ALS mice, dietary Mg2Si intervention markedly ameliorates motor dysfunction and effectively delays disease progression. Collectively, this study firstly applies Mg2Si nanomaterial-based sustained hydrogen therapy for ALS treatment, establishes a novel gastrointestinal hydrogen delivery strategy, and provides an innovative and clinically translatable paradigm for the design of hydrogen delivery systems against neurodegenerative disorders.\n\nID: 42381982\nTitle: Antioxidant Nanozymes: From Rational Design to Biomedical Applications.\nAbstract: Antioxidant nanozymes regulate reactive oxygen species homeostasis by mimicking the core catalytic functions of natural antioxidant enzymes, including superoxide dismutase-, catalase-, and glutathione peroxidase-like activities. The clinical translation of natural antioxidant enzymes has long been hampered by inherent limitations: short in\u00a0vivo half-life, susceptibility to inactivation under physiological conditions, cumbersome purification processes, high production costs, non-negligible immunogenicity, and limited targeting capacity. In contrast, antioxidant nanozymes can overcome these bottlenecks with superior structural stability, tunable catalytic activity, low preparation cost, and flexible multifunctional modification. Guided by the catalytic mechanisms of natural enzymes, researchers have established rational design strategies for antioxidant nanozymes. To date, a diverse array of antioxidant nanozymes have been developed, with promising applications in multiple biomedical fields, including inflammatory diseases, ischemia-reperfusion injury, neurodegenerative disorders, and cancer adjuvant therapy. Notably, landmark clinical progress has been achieved: The catalytic nanocrystal suspension CNM-Au8, a therapeutic candidate for amyotrophic lateral sclerosis, has advanced to phase II clinical trials. This review systematically summarizes the core catalytic mechanisms of antioxidant nanozymes, clarifies the structure-activity relationships between rational material design and catalytic performance, reviews the latest advances in their biomedical applications, and dissects the key bottlenecks restricting preclinical research and clinical translation. It aims to provide rational design principles for researchers in this field, reduce empirical trial and error in material development, and provide guidance for the further optimization and clinical translation of antioxidant nanozymes.\n\nID: 42329291\nTitle: Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.\nAbstract: Major neurodegenerative disorders, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are pathologically driven by mitochondrial failure and persistent neuroinflammation. Defects in oxidative phosphorylation, excess Reactive Oxygen Species (ROS), and impaired mitophagy cause an imbalance in neuronal energy and promote the release of mitochondrial Damage-Associated Molecular Patterns (DAMPs) that activate microglial inflammasomes and enhance inflammatory signalling. Current therapeutic strategies have largely targeted individual pathways and have been unable to effectively modulate this interrelated mitochondrial immune axis or achieve efficient delivery to the Central Nervous System (CNS). This review addresses the dual promise of berberine therapy, a biologically active plant alkaloid that enhances mitochondrial production via AMPK/PGC-1\u03b1 and SIRT1, restores membrane potential, promotes mitophagy, and inhibits NF-\u03baB and NLRP3-mediated inflammation. Nevertheless, this compound's weak solubility, limited bioavailability, and extremely poor Blood-Brain Barrier (BBB) penetration limit its therapeutic application. Encapsulation of berberine in polymeric nanoparticles, including Polyethylene glycol (PEG)-based polymeric nanoparticle systems, offers improved stability, bioavailability, and targeted mitochondrial delivery. An effective method for reducing neuroinflammation and mitochondrial dysfunction is this comprehensive phytochemical nanotechnology technique.\n\nID: 42302791\nTitle: ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.\nAbstract: Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.\n\nID: 42274734\nTitle: [Anti-infectious cross-linking: when and how? : PACK-CXL as treatment option for infectious keratitis].\nAbstract: Infectious keratitis remains a\u00a0major cause of blindness worldwide. Conventional antimicrobial treatment is not always sufficient, particularly against drug-resistant pathogens. Photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL) offers a\u00a0promising adjunctive or alternative treatment. Narrative review based on the current literature and clinical experience, covering mechanisms of action, clinical evidence, protocol selection and practical decision-making criteria for PACK-CXL. The PACK-CXL acts via three mechanisms: direct killing of pathogens through reactive oxygen species (ROS), increased resistance to protease digestion through steric hindrance and anti-inflammatory effects. Clinical studies demonstrated that adjuvant PACK-CXL shortens the healing time and as monotherapy achieves approximately 89% success in small bacterial ulcers. Higher total radiation doses (high fluence, \u2265\u202f7.2\u202fJ/cm2) are more effective than the standard protocol (5.4\u202fJ/cm2). For Acanthamoeba keratitis, a\u00a0sequential dual chromophore strategy (riboflavin/UV followed by Rose bengal/green light) shows promising results. The use of PACK-CXL enables rapid, largely pathogen-independent treatment of infectious keratitis. Protocol selection should be guided by ulcer size, depth and pathogen type. Accelerated high-fluence protocols are particularly suitable for antimicrobial use. HINTERGRUND: Die infekti\u00f6se Keratitis stellt weltweit eine h\u00e4ufige Ursache f\u00fcr rechtliche Erblindung dar. Herk\u00f6mmliche Therapien mit Breitspektrumantimikrobiotika sind nicht immer ausreichend wirksam, insbesondere bei therapieresistenten Erregern. Das photoaktivierte Chromophor-Keratitis-Crosslinking (PACK-CXL) bietet eine vielversprechende Erg\u00e4nzung oder Alternative zur konventionellen Therapie. Die \u00dcbersichtsarbeit basiert auf aktueller Literatur und klinischer Erfahrung. Es werden die Wirkmechanismen, klinische Evidenz, Protokollwahl und praktische Entscheidungskriterien f\u00fcr PACK-CXL dargestellt. PACK-CXL wirkt \u00fcber 3\u00a0Mechanismen: direkte Pathogenabt\u00f6tung durch reaktive Sauerstoffspezies (ROS), erh\u00f6hte Resistenz gegen Proteaseverdauung durch sterische Behinderung und antiinflammatorische Effekte. Klinische Studien zeigen, dass PACK-CXL als adjuvante Therapie die Heilungszeit verk\u00fcrzt und als Monotherapie bei kleinen bakteriellen Ulzera eine Erfolgsrate von 89\u202f% erreicht. H\u00f6here Gesamtstrahlendosen (\u201ehigh fluence\u201c) (\u2265\u202f7,2\u202fJ/cm2) sind wirksamer als das Standardprotokoll (5,4\u202fJ/cm2). Bei Akantham\u00f6benkeratitis zeigt eine sequenzielle Dualchromophor-Strategie (Riboflavin/UV gefolgt von Bengalrosa/Gr\u00fcnlicht) vielversprechende Ergebnisse. PACK-CXL erm\u00f6glicht eine schnelle, weitgehend erregerunabh\u00e4ngige Behandlung infekti\u00f6ser Keratitiden. Die Wahl des Protokolls sollte sich an Ulkusgr\u00f6\u00dfe, -tiefe und Erregertyp orientieren. Beschleunigte High-fluence-Protokolle sind f\u00fcr den antimikrobiellen Einsatz besonders geeignet.\n\nID: 42264545\nTitle: Nanotechnology-enabled targeting strategies for neurodegenerative disorders: role of functionalized nanoparticles.\nAbstract: Neurodegenerative disorders comprise a diverse group of progressive neurological diseases characterized by the gradual loss of neuronal structure and function. Conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis arise from multifactorial mechanisms involving genetic susceptibility, environmental factors, and age-related cellular decline. Key pathogenic processes include oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, impaired axonal transport, Golgi fragmentation, and chronic neuroinflammation, all of which disrupt neuronal homeostasis and synaptic communication, ultimately leading to neuronal death. Hormonal imbalances further exacerbate these effects by promoting oxidative damage, inflammation, and metabolic dysfunction. Despite advances in understanding disease mechanisms, effective drug delivery remains challenging due to the restrictive nature of the blood-brain barrier. Recent developments highlight the potential of nanoparticle-based drug delivery systems to overcome these limitations. Functionalized nanoparticles enhance blood-brain barrier penetration, improve targeting specificity, and enable controlled drug release. These systems can deliver neuroprotective agents, antioxidants, peptides, and gene therapies directly to affected brain regions. Thus, integrating disease pathophysiology with nanotechnology-based strategies offers a promising approach for improving therapeutic outcomes and advancing precision treatment in neurodegenerative disorders.\n\nID: 42248860\nTitle: TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.\nAbstract: Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation\u00a0at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules\u00a0binding\u00a0to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1\u00a0to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the\u00a0phosphatase PP1\u00a0to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).\n\nID: 42236747\nTitle: Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.\nAbstract: Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.\n\nID: 42228326\nTitle: FUS modulates R-loops by functionally interacting with RNase H1.\nAbstract: R-loops are three-stranded nucleic acid structures consisting of an RNA:DNA hybrid and a displaced single-stranded DNA, typically formed during transcription. Emerging evidence indicates that R-loops are not merely transcriptional byproducts, but serve as functional regulatory structures that influence chromatin organization, transcriptional pausing, and RNA processing. However, dysregulated accumulation of R-loops can induce DNA damage and genomic instability, necessitating precise mechanisms for their regulation. This study aims to elucidate the role of the RNA-binding protein FUS (Fused in Sarcoma), a protein mutated in Amyotrophic Lateral Sclerosis (ALS) and cancer, in modulating R-loop dynamics. Knockdown of FUS in HeLa cells resulted in a significant increase in global R-loop levels, as assessed by immunofluorescence and dot blot assays. Proximity ligation assay (PLA) demonstrated that FUS is in close proximity to R-loops and nascent RNA. Further, FUS was found to interact with RNase H1, a key endonuclease involved in R-loop resolution, in an R-loop dependent manner, as demonstrated by PLA and co-immunoprecipitation assay. Importantly, in vitro assays show that FUS enhances RNase H1-mediated degradation of RNA:DNA hybrids. Moreover, FUS depletion reduces RNase H1 proximity to elongating RNA polymerase II, suggesting altered engagement of RNase H1 with the transcription machinery. These findings highlight a crucial role for FUS-RNase H1 axis in regulating R-loop levels, providing insights into the potential mechanisms underlying R-loop-associated pathologies in neurodegenerative diseases linked to FUS.\n\nID: 42489267\nTitle: A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.\nAbstract: Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500\u00a0000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.\n\nID: 42476327\nTitle: Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.\nAbstract: Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-\u03baB, PI3K-Akt-mTOR, MAPK and Wnt/\u03b2-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.\n\nID: 42469634\nTitle: Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-\u03baB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder driven by neuroinflammation involving activated microglia and astrocytes, which accelerates the loss of motor neurons. While Secretory leukocyte protease inhibitor (SLPI) is known for its immunomodulatory properties, its specific role in ALS pathogenesis has not been fully established. This study aimed to characterize the expression patterns and functional significance of SLPI in ALS models. The study utilized SOD1G93A mice to analyze the spatiotemporal dynamics of SLPI expression in the gastrocnemius muscle, lumbar spinal cord, and serum across different disease stages. In vitro functional assays were conducted using siRNA-mediated knockdown of SLPI in BV2 (microglia), MA (astrocytes), and NSC-34 (motor neurons) cell lines. Additionally, recombinant SLPI protein was applied to LPS-stimulated BV2 cells to investigate its effect on the TLR4/ NF-\u03baB signaling pathway. In SOD1G93A mice, SLPI was significantly upregulated in the gastrocnemius muscle from the pre-symptomatic stage (60 days) through the late stage (130 days). In the lumbar spinal cord, SLPI showed a transient initial increase but declined sharply by the end-stage; a similar significant reduction was observed in late-stage serum levels. In vitro, SLPI knockdown exacerbated pro-inflammatory cytokine production in all three cell types and impaired the antioxidant capacity of NSC-34 motor neurons. Mechanistically, recombinant SLPI attenuated inflammation in BV2 cells by modulating the TLR4/NF-\u03baB pathway. The dynamic changes in SLPI levels suggest its potential relevance as a candidate molecule for disease staging. Meanwhile, its protective effects in regulating inflammation suggest that it could be a promising therapeutic candidate for mitigating ALS-associated neuroinflammation.\n\nID: 42467293\nTitle: Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.\nAbstract: Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-\u03baB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.\n\nID: 42462180\nTitle: Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS.\nAbstract: CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform-capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes-could validate previously proposed biomarkers and identify additional candidates relevant to ALS. Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls. The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases-particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature. Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.\n\nID: 42458512\nTitle: Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.\nAbstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD. The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-\u03baB) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS. DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-\u03baB-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE. DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.\n\nID: 42451086\nTitle: Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.\nAbstract: Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.\n\nID: 42450002\nTitle: Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.\nAbstract: Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.\n\nID: 42448407\nTitle: Small molecular therapeutic targets for neurodegenerative diseases.\nAbstract: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis disease are characterized by progressive neuronal loss, protein aggregation, and synaptic dysfunction. These diseases share common pathological mechanisms including oxidative stress, mitochondrial impairment, chronic neuroinflammation, protein misfolding, and epigenetic dysregulation. Current therapies offer only symptomatic relief and fail to halt disease progression. Recent advances in transcriptomics and proteomics have enabled the identification of shared molecular pathways and druggable targets across multiple neurodegenerative diseases. The key targets, such as BDNF-TrkB, TREM2, SIRT1, PINK1-Parkin, GSK-3\u03b2, NLRP3, and mTOR have shown promise in preclinical models, offering opportunities for broad-spectrum therapeutic development. Importantly, blood-brain barrier disruption and neuroinflammatory crosstalk exacerbate disease pathology and hinder drug delivery. Innovative strategies involving nanocarriers, gene therapy, and epigenetic modulation are emerging to overcome these barriers. This review highlights the convergence of disease mechanisms, discusses common molecular signatures and therapeutic vulnerabilities, and explores novel small molecular interventions targeting shared pathways mainly in AD and PD. A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.\n\nID: 42443387\nTitle: Astrocytic lipid dysregulation as an early driver of neurodegeneration.\nAbstract: Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.\n\nID: 42442908\nTitle: Role of ESCRT pathway and autophagy in neurodegenerative diseases.\nAbstract: Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.\n\nID: 42430091\nTitle: The Role of PGC-1\u03b1 in Neurodegenerative Diseases: Molecular Mechanisms, Translational Challenges, and Therapeutic Potential.\nAbstract: Neurodegenerative diseases (NDDs) are progressive disorders in which mitochondrial dysfunction, oxidative stress, proteostasis failure, neuroinflammation, and synaptic damage progressively interact to drive neuronal vulnerability. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\u03b1) links metabolic adaptation to stress-response pathways that are repeatedly disrupted in Alzheimer's disease, Parkinson's disease, Huntington's disease, polyglutamine (PolyQ) disorders, and amyotrophic lateral sclerosis. Rather than providing only an updated catalogue of studies, this review organizes the evidence into a cross-disease rheostat framework that explains why PGC-1\u03b1 modulation is protective in some settings but incomplete or maladaptive in others. Current findings indicate that PGC-1\u03b1 supports mitochondrial biogenesis, oxidative phosphorylation, antioxidant defense, mitophagy, autophagy, protein quality control, and inflammatory balance. However, its effects are highly context dependent. In several models, restoration of PGC-1\u03b1-related signaling improves mitochondrial function and reduces neuronal injury, whereas broad, sustained, or cell-inappropriate activation may produce limited benefit or undesirable outcomes. These observations suggest that PGC-1\u03b1 is not a simple neuroprotective switch, but a flexible regulatory hub whose therapeutic value depends on cell type, isoform profile, disease stage, and activation level. Emerging strategies, including small-molecule modulators, gene delivery, antisense-based approaches, nanoparticle systems, and exercise-related interventions, remain largely preclinical and face major barriers related to CNS delivery, pathway selectivity, dose and cell-type control, peripheral safety, and validated target-engagement biomarkers. Nevertheless, clinical translation requires stronger causal validation, reliable target-engagement biomarkers, selective delivery methods, and long-term safety assessment. Future research should focus on precision-based modulation of PGC-1\u03b1 to determine when and how this pathway can be safely used for disease modification. Such a careful approach may help transform PGC-1\u03b1 from a broad experimental target into a clinically relevant strategy for well-defined neurodegenerative phenotypes.\n\nID: 42428879\nTitle: From Air to Brain: Environmental Nanoparticles as Modifiable Risk Factors for Neurodevelopmental, Neurodegenerative, and Mental Disorders.\nAbstract: Ultrafine particles (\u2264100 nm) and other environmental nanoparticles have emerged as biologically active pollutants that can cross biological barriers, including the blood-brain barrier and the placenta. Growing evidence implicates ultrafine particles in a wide range of neuropsychiatric conditions, yet their effects remain poorly integrated into clinical and public health frameworks. In this review, we distinguish between size-defined ultrafine particles (UFPs, \u2264100 nm), composition-defined environmental nanoparticles originating from combustion and secondary formation processes, and engineered nanomaterials (ENPs), which differ in physicochemical properties, exposure scenarios, and regulatory status. This narrative systematic review synthesizes findings from human and experimental studies on the neuropsychiatric and neurodevelopmental effects of environmental nanopollutants. A structured search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to November 2025, following explicit inclusion and exclusion criteria. Eligible studies included peer-reviewed human and animal research assessing mental health or neurological outcomes of nanopollutant exposure. Epidemiological studies\ue5f8primarily involving traffic-related air pollution and mixed combustion-derived ultrafine particle exposures\ue5f8suggest associations with increased risk of cognitive impairment, autism spectrum disorder, depression, schizophrenia, and neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Prenatal and early life exposures were linked to cortical thinning, altered neurodevelopmental trajectories, and early proteinopathies. Underlying mechanisms include neuroinflammation, oxidative stress, and protein aggregation. Despite methodological heterogeneity, the evidence supports the urgent need for regulation and prevention. Environmental nanopollutants constitute an under-recognized, modifiable risk factor for neuropsychiatric and neurodegenerative conditions. A paradigm shift is needed to incorporate environmental exposure history into mental health research, risk assessment, and prevention strategies. Regulatory action targeting nanopollutant emission and exposure, particularly in vulnerable populations, is critical to mitigating long-term neurological consequences.\n\nID: 42419491\nTitle: The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?\nAbstract: Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.\n\nID: 42411953\nTitle: Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.\nAbstract: We report the clinicopathological and biochemical findings of ALS associated with a UBQLN2 P494L mutation. Autopsy revealed widespread TDP-43 pathology and UBQLN2-positive inclusions. Immunoblot analysis demonstrated a marked reduction of soluble UBQLN2, supporting functional UBQLN2 insufficiency as a pathogenic mechanism underlying TDP-43 aggregation.\n\nID: 42393897\nTitle: Bioinformatic Identification of Shared Gene Networks Between Weaning- Induced Intestinal Inflammation and Neuroinflammatory-Related Pathways.\nAbstract: Weaning is a critical developmental stage that can trigger intestinal inflammation through disruption of microbial homeostasis, immune responses, and epithelial barrier integrity. While numerous studies have explored gene expression changes during weaning in animals, no comparable analyses have been conducted in humans. Given the close physiological and genetic similarity between pigs and humans, piglet data were employed to investigate the molecular mechanisms underlying weaning-induced intestinal inflammation and its potential links to neurological pathways. A curated set of 117 differentially expressed genes related to gut inflammation was collected from bibliographic sources. Protein-protein interaction network analysis was performed using NetworkAnalyst and Cytoscape, followed by hub gene selection and functional enrichment using KOBAS, ClusterProfiler, and StringApp. Among the identified hub genes, SOD1, CAT, TNF, CXCR4, TLR2, and TGFB1 play key roles in oxidative stress, immune response, glial regulation, and neuroinflammatory signaling. Enrichment analysis revealed significant associations with pathways such as Amyotrophic Lateral Sclerosis, TGF-\u03b2 signaling, Folate and Vitamin B12 metabolism, and Inflammatory Bowel Disease, as well as biological processes like gliogenesis, hypoxia response, and cytokine signaling. These findings suggest that intestinal inflammation during weaning may have systemic implications, highlighting shared molecular pathways relevant to neuroinflammatory-related processes. This study provides new insight into the genetic and molecular landscape of weaning-induced inflammation and its broader systemic effects. The identified shared molecular pathways may provide a foundation for future experimental studies investigating the broader biological implications of early-life intestinal inflammation.\n\nID: 42386657\nTitle: The SQSTM1 L341V Variant Associated With Sporadic ALS Promotes the Accumulation of Enlarged Ubiquitin-Positive SQSTM1 Bodies.\nAbstract: SQSTM1 is one of the causative genes of neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The SQSTM1 protein regulates the degradation of polyubiquitinated proteins and autophagosome formation through its interaction with microtubule-associated protein light chain 3 (MAP1LC3/LC3). However, the molecular mechanisms by which SQSTM1-LC3 binding regulates the autophagy-endolysosomal system (APELS) remain unclear. To elucidate the spatiotemporal role of SQSTM1, we transiently expressed wild-type SQSTM1 or missense mutants carrying mutations in the LC3-interacting region (LIR), fused with the photoconvertible fluorescent protein Dendra2. Live-cell fluorescence imaging and co-localization analyses with markers of the APELS were then performed. Particle analysis of photoconverted or non-photoconverted SQSTM1-positive structures in live cells revealed that the pathogenic L341V variant formed larger structures than the wild-type. Co-localization analyses further showed that both the L341V and artificial LIR3A mutants accumulated in large ubiquitin-positive structures, likely due to impaired localization to autophagosomes. These results suggest that mutations within the LIR differentially affect autophagosome formation and cargo degradation within APELS-related compartments, highlighting the importance of SQSTM1 structural integrity in ALS/FTD pathogenesis.\n\nID: 42373582\nTitle: Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.\nAbstract: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43-positive inclusion and the cystatin C-positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co-occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti-amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post-mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.\n\nID: 42368190\nTitle: Atypical involvement of Alzheimer's tau proteins in diseases beyond tauopathies.\nAbstract: Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed \"tauopathy\", including Alzheimer's disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the \"atypical\" pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.\n\nID: 42365390\nTitle: Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.\nAbstract: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression. To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent \"prion-like\" spreading of aggregates. The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival. Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.\n\nID: 42360551\nTitle: Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.\nAbstract: Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant\u00a0mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for\u00a0disease-modifying or adjunctive strategies, rather than curative approaches.\n\nID: 42353250\nTitle: Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives.\nAbstract: The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 was recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management.\n\nID: 42349423\nTitle: Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics.\nAbstract: The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific genetic diseases. To remedy this, an alternative approach of reverse phenotypic mapping was tested: Compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in FTD/ALS type 3 models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries.\n\nID: 42349421\nTitle: Rewiring ALS by modulating the autophagy receptor SQSTM1.\nAbstract: Drug screening for genetic disorders is limited by difficulty identifying disease-relevant phenotypes. In this issue, Roussange et al., show that reverse phenotypic mapping could uncover therapeutic gene expression signatures. Using this approach, they identified prazosin, which increases SQSTM1 expression and rescues disease phenotypes in iPSC-derived motor neurons and zebrafish model of amyotrophic lateral sclerosis with SQSTM1 haploinsufficiency.\n\nID: 42347120\nTitle: RNA-Binding Proteins in Ageing and Age-Related Disease.\nAbstract: RNA-binding proteins (RBPs) are essential regulators of all aspects of RNA metabolism, including splicing, stability, localisation, translation, and degradation. Through their ability to recognise specific cis-elements in target transcripts, often via RNA-recognition motifs or other conserved domains, RBPs enable rapid cellular adaptation to stress and maintain proteostasis, particularly in post-mitotic tissues with limited transcriptional flexibility. Accumulating evidence positions RBPs as both modulators and drivers of the molecular hallmarks of ageing, including genomic instability, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and chronic inflammation. This review synthesises peer-reviewed studies on the multifaceted roles of RNA-binding proteins in organismal ageing and age-related diseases. Key themes include the tissue- and age-dependent changes in expression of turnover and translation regulatory RBPs such as HuR (ELAVL1), AUF1 (HNRNPD), TIA-1, and tristetraprolin (ZFP36), which alter the stability of mRNAs encoding cell-cycle regulators, pro-inflammatory cytokines, and stress-response proteins. Systematic downregulation of core splicing factors, including PTBP1 and several heterogeneous nuclear ribonucleoproteins, drives widespread senescence-associated splicing alterations in pathways governing cell division, autophagy, DNA repair, and mitochondrial function, suggesting a causal contribution to the senescent phenotype. Prion-like RBPs such as TDP-43 and FUS exhibit age-dependent mislocalisation, nuclear depletion, and cytoplasmic aggregation, contributing to splicing defects, impaired RNA transport, and neurodegeneration in amyotrophic lateral sclerosis, frontotemporal dementia, and limbic-predominant age-related TDP-43 encephalopathy. Interactions between RBPs and non-coding RNAs, together with disrupted liquid-liquid phase separation dynamics, further exacerbate age-related decline. By integrating mechanistic studies from cellular and animal models with observations in human cohorts, this review underscores RBPs as central nodes linking multiple ageing hallmarks and highlights their potential as biomarkers and therapeutic targets to promote healthy ageing. Limitations of current models and priorities for future translational research are discussed.\n\nID: 42384233\nTitle: Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapies, emphasizing the need for deeper understanding of disease pathogenesis. While more than 40 ALS-associated genes have been identified, their contribution varies significantly across populations and the data from the Indian population remains scarce. We aimed to comprehensively characterize the spectrum of coding DNA variations in ALS-associated genes and identify novel genetic contributors in an Indian cohort. Whole-exome sequencing on 761 ALS patients and 917 in-house healthy controls and repeat-primed PCR for expansions (C9orf72, ATXN2, NOTCH2NLC, NOP56) were performed. Variants were classified using ACMG guidelines, and rare variant association testing was conducted. Overall diagnostic yield was 15.90%, with pathogenic/likely pathogenic variants. Familial ALS showed higher diagnostic yield (36.95%) than sporadic ALS (12.96%). SOD1 dominated familial cases (53.85%), while OPTN, SOD1 and FIG4 were prevalent in sporadic cases. Homozygous SOD1 variants in six patients correlated with juvenile/young onset (<\u200930 years). C9orf72 expansions (4%) and ATXN2 repeats (1.7%) were identified at frequencies comparable with Asian cohorts. Rare variant analysis identified JAK2 as a novel genome-wide significant signal (FDR\u2009=\u20093.5\u2009\u00d7\u200910-5). This first large-scale genomic survey of Indian ALS patients showed SOD1 being the predominant cause of fALS, while OPTN, FIG4, and other genes drive disease amidst low C9orf72 frequency. The novel JAK2 association suggests a potential neuroinflammatory mechanism, highlighting the importance of studying diverse populations to uncover distinct genetic etiologies.\n\nID: 42310298\nTitle: Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.\nAbstract: G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42469095\nTitle: Lysosome as a central hub in ferroptosis-driven pathologies.\nAbstract: Ferroptosis is a unique form of programmed cell death that involves multiple organelles. Although traditionally viewed as a 'degradation workshop', accumulating evidence reveals that the lysosome serves as a central hub for iron metabolism and signal transduction, orchestrating the overall fate of cellular ferroptosis across spatiotemporal dimensions. In this review, we propose the concept of the 'lysosome-ferroptosis axis' and outline its roles in metabolic signaling, autophagy, and lysosomal membrane permeabilization. We further discuss the involvement of this axis in neurodegenerative, tumor, and cardiometabolic diseases, with the aim of providing new insights for targeted therapeutic strategies.\n\nID: 42465575\nTitle: Metabolic sovereignty through oxidative hostility: a mechanistic perspective on how cancer engineers stromal dependency via ROS-mediated lysosomal reprogramming.\nAbstract: Cancer cells orchestrate a profound remodeling of their microenvironment to suppress immune surveillance and create metabolic dependency in surrounding stroma. We propose a mechanistic hypothesis in which this transformation is driven by a coordinated reactive oxygen species (ROS) signaling cascade. Cancer cells generate superoxide (O2\u2022-) through NADPH oxidase (NOX) upregulation and mitochondrial respiration. Superoxide is rapidly converted to hydrogen peroxide (H2O2), a stable, membrane-diffusible ROS species that crosses stromal cell membranes via aquaporin channels. Within cancer-associated fibroblasts (CAFs), H2O2 triggers controlled lysosomal membrane permeabilization (LMP), releasing catalytic iron and initiating iron-catalyzed Fenton chemistry that converts this signal into reactive lipid-peroxidation products, which in turn activate PGC-1\u03b1 and drives a profound shift in CAF metabolism toward fatty acid oxidation (FAO). Through this cascade, CAFs become predominantly FAO-dependent, producing acetyl-CoA, NADPH, and ATP that fuel tumor growth while simultaneously generating a lactate-enriched, acidic, nutrient-depleted microenvironment hostile to immune function. We present three converging lines of evidence supporting this mechanism and provide four experimentally falsifiable predictions, including a critical iron chelation experiment designed as the crucial mechanistic validation of the cascade. If validated, this framework redefines immunotherapy resistance as a metabolic infrastructure problem-not only an immune cell problem-and predicts that targeting stromal metabolic engineering in combination with checkpoint blockade may circumvent resistance in cold tumors.\n\nID: 42449433\nTitle: Targeting lysosome-dependent cell death in cancer: towards therapeutic strategies.\nAbstract: Lysosomes serve as central degradative hubs in cells, playing critical roles in maintaining protein homeostasis, clearing damaged organelles, and regulating metabolic signaling. Tumor cells heavily rely on lysosomal functions during proliferation, invasion, and drug resistance, a dependency that concurrently endows them with inherent susceptibility to lysosomal membrane permeabilization (LMP). Current cancer therapies rely heavily on surgical resection for early-stage disease, and chemotherapy or radiotherapy for advanced-stage cancers, but these modalities are limited by poor efficacy, severe side effects, and drug resistance. Therefore, targeting LMP to induce lysosome-dependent cell death (LDCD) represents a promising breakthrough. This review systematically summarizes the molecular mechanisms underlying LMP initiation and execution, as well as the regulatory pathways of LDCD modalities, including apoptosis, necroptosis, ferroptosis, pyroptosis, immunogenic cell death, and autophagy-dependent death. It further highlights the dual roles of lysosomes and LDCD in the tumor microenvironment and their core functions in tumor progression. Additionally, we outline classic therapeutic strategies targeting LMP and novel lysosome-targeting technologies, and discuss combination therapy regimens based on lysosomal modulation. These advances provide comprehensive theoretical foundations and new insights for the development of broad-spectrum lysosome centered anticancer drugs.\n\nID: 42442908\nTitle: Role of ESCRT pathway and autophagy in neurodegenerative diseases.\nAbstract: Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.\n\nID: 42388368\nTitle: Lysosomal aggregation of iron nanoparticles guided by multistage transformation induces potent ferroptosis.\nAbstract: Ferroptosis, a cell death form driven by lipid peroxidation accumulation via iron-dependent Fenton reaction, has attracted substantial attention in cancer therapy. This process is strictly dependent on iron ion concentration and environmental acidity. However, the relatively weak acidity in the tumor cytoplasm may significantly impair the Fenton catalytic activity of endocytosed iron-based nanoparticles. Inspired by the intrinsic acidic vesicular compartments of tumoral lysosomes, a multistage size-switching strategy is proposed to effectively target the optimal \"battlefields\" for iron-based materials. Through rational engineering, nanotransformers (NTF) integrated with collagenase (CLG) achieve targeted disassembly for deep tumor penetration and lysosomal aggregation to sustain Fenton catalytic activity. Enlarged iron depots in lysosomes prevent exocytosis, ensuring prolonged catalytic generation of lipid peroxidation species to initiate and amplify ferroptosis, ultimately inducing lysosomal membrane permeabilization and altered organelle functions. Further analysis reveals that iron nanoparticle lysosomal aggregation-mediated ferroptosis can effectively trigger immunogenic cell death and elicit robust antitumor immune responses. This work demonstrates the potential of well-designed multistage size-switchable nanotransformers in cancer treatment, representing a paradigm shift in advancing iron-based nanoparticle-mediated ferroptosis therapy.\n\nID: 42375608\nTitle: Lysosome-dependent cell death in hepatocellular carcinoma: unlocking the therapeutic potential of natural products.\nAbstract: Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world, and the available targeted therapies (e.g., sorafenib, lenvatinib) have limited options and frequent drug resistance. Lysosome-dependent cell death (LDCD), characterized by increased lysosomal membrane permeabilization (LMP) and the release of proteases, has attracted considerable attention as a non-apoptotic mechanism that can circumvent drug resistance. In recent years, researchers have used natural compounds in the treatment of HCC, which effectively induce LDCD through a variety of mechanisms, such as acid sphingomyelinase inhibition, lysosomal-iron-ferroptosis axis activation, lysosomal pH regulation, PI3K/AKT/mTOR-TFEB pathway inhibition and so on. These compounds synergize with conventional targeted agents to overcome drug resistance through direct cytotoxicity or targeting hypertrophic lysosomal drug release. This article reviews the regulation of LDCD and the role of natural products in HCC based on PubMed, Web of Science and CNKI databases, aiming to providing a reference for the treatment of drug-resistant liver cancer.\n\nID: 42372730\nTitle: Two parallel neuronal circuits involving electrical synapse and DAF-7/TGF-\u03b2 signaling regulate muscle autophagy in C. elegans.\nAbstract: The systemic coordination of autophagy during development remains poorly understood. Here, we identify two parallel neuronal circuits that regulate the autophagy-lysosome pathway in the body wall muscle of C. elegans. One circuit, utilizing UNC-7/UNC-9 electrical synapses between AVA interneurons and A-type motor neurons (A-MNs), promotes autophagy by inhibiting neuropeptide release from A-MNs. The other employs the TGF-\u03b2-like molecule DAF-7, secreted from ASI sensory neurons, which activates autophagy via the canonical TGF-\u03b2 pathway. These pathways converge to regulate cytosolic Ca\u00b2\u207a levels in the muscle, thereby maintaining lysosomal integrity. Disruption of either circuit elevates Ca\u00b2\u207a, overactivating calpain. This leads to the accumulation of non-degradative autolysosomes and accelerates muscle degeneration. Our findings elucidate a neuronal mechanism for controlling muscle autophagy and provide insights into the pathogenesis of neurogenic myopathy.\n\nID: 42365390\nTitle: Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.\nAbstract: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression. To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent \"prion-like\" spreading of aggregates. The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival. Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.\n\nID: 42357358\nTitle: Magnetic Fields in Cancer Therapy: Mechanistic Insights, Signaling Pathways, and Evidence from Clinical and In Vitro Studies.\nAbstract: Magnetic fields (MFs) represent an emerging modality in cancer therapy, encompassing static, low-frequency, pulsed, and nanoparticle-mediated alternating fields. These interventions have demonstrated the capacity to modulate proliferation, apoptosis, ferroptosis, migration, and epithelial-to-mesenchymal transition (EMT) in tumor cells, often through reactive oxygen species (ROS) modulation, ion channel regulation, membrane receptor dynamics, and lysosomal membrane permeabilization. Magnetic nanoparticle hyperthermia (MHT) has reached clinical application, showing promising outcomes in glioblastoma and prostate cancer, while pulsed electromagnetic fields (PEMFs) and magneto-mechanical approaches are under preclinical investigation. The mechanistic diversity of MFs allows synergistic combination with chemotherapy, radiotherapy, and immunotherapy. However, parameter sensitivity, field standardization, and long-term safety remain challenges. Here, we review mechanistic insights, signaling pathways, and experimental and clinical evidence for MF-based cancer therapies, highlighting translational potential and the need for rigorous optimization to realize clinical efficacy.\n\nID: 42350373\nTitle: Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.\nAbstract: Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.\n\nID: 42320631\nTitle: Nrf2 dynamically regulates RANKL-induced osteoclastogenesis and cathepsin K function.\nAbstract: Osteoclasts mediate bone resorption primarily through the protease Cathepsin K. RANKL, the master cytokine driving osteoclastogenesis, elevates reactive oxygen species (ROS) levels that promote osteoclast differentiation; however, excessive ROS can lead to oxidative stress and cellular damage. To counteract the detrimental effects of ROS, osteoclasts activate antioxidant defense mechanisms, including the NRF2 pathway. Here, we identify that antioxidant responses are dynamically regulated during osteoclastogenesis and osteoclast activation. Through a combined bioinformatic and genetic approach using engineered mouse models, we demonstrate a dual role of RANKL in regulating antioxidant responses in osteoclasts: while it suppresses glutathione-mediated antioxidant defenses, RANKL activates Nrf2-dependent mechanisms during osteoclast differentiation. Genetic deletion of Nrf2 (Nfe2l2) in vitro enhances osteoclast formation, whereas impairs osteoclast resorptive function, reducing cathepsin K activity. Nrf2-deficient osteoclasts exhibit increased lipid peroxidation, mitochondrial dysfunction, and lysosomal instability without alterations in cell viability. Together, these findings identify NRF2 as a critical regulator of osteoclast function, essential for maintaining redox balance and lysosomal integrity during bone resorption. This study reveals an intricate interplay between RANKL-induced oxidative signaling and antioxidant regulation, highlighting NRF2 as a critical determinant of osteoclast-mediated bone resorption.\n\nID: 42259771\nTitle: Characterization of programmed cell death pathways activated in Mycobacterium tuberculosis-infected human macrophages.\nAbstract: Mycobacterium tuberculosis (Mtb) primarily infects human lung macrophages, which serve as its major replication niche. Mtb can manipulate host macrophage cell death pathways to its advantage by inhibiting apoptosis and inducing necrotic cell death. However, the specific necrotic cell death pathway activated in human macrophages after Mtb infection remains unclear. Here, we used the THP-1 cell line and primary human monocyte-derived macrophage (hMDM) to analyze multiple programmed cell death pathways during days 1-3 after Mtb infection. Confocal microscopic analysis demonstrates that Mtb-infected THP-1 cells or hMDMs rarely exhibited apoptosis. Immunoblotting shows that Mtb induces significant CASP3 and GSDME activation in THP-1 cells, but not in hMDMs. We show that Mtb, in THP-1 cells but not hMDM, induces a significant increase in GSDMD cleavage, a hallmark of pyroptosis. MLKL phosphorylation was not observed in THP-1 cells or hMDMs during Mtb infections, indicating an absence of necroptosis. No changes in ferroptosis markers such as GPX4 expression or lipid peroxidation levels were detected. Time-lapse live-cell imaging revealed no lysosomal membrane permeabilization prior to plasma membrane rupture (PMR). However, we observed DNA release from Mtb-infected THP-1 cells and hMDMs after PMR. The DNA released from THP-1 cells exhibits low levels of myeloperoxidase and histone H3 citrullination. High-resolution confocal imaging shows that Mtb is associated with the released DNA. We demonstrate that pyroptosis induction in THP-1 cells is dispensable for the DNA release and cell death induction. In conclusion, our results reveal that Mtb-triggered cell death in hMDMs bypasses canonical cell death pathways like apoptosis, pyroptosis, necroptosis, and ferroptosis. Instead, cell death in both THP-1 cells and hMDMs correlates with DNA release, potentially similar to NETosis in neutrophils.\n\nID: 42251472\nTitle: Light-Driven Photosensitive Materials Induce Lysosome Escape for Tumor Treatment.\nAbstract: Lysosomes, as a key acidic organelle which was responsible for intracellular degradation and recycling, often intercept small-molecule drugs or nanoparticle drugs, limiting the therapeutic efficacy of cancer. To overcome this barrier, lysosomal rupture has emerged as a novel phototherapy strategy due to its noninvasive and spatiotemporally controllable nature. This review provides a comprehensive summary of photosensitive materials capable of modulating lysosomal membrane permeability upon light irradiation, focusing on two primary categories: nanomaterials and small molecules. These lysosome-targeting photosensitive materials can trigger multiple cell death pathways (apoptosis, necrosis, pyroptosis, and ferroptosis) by photodynamic or photothermal therapy, thereby enhancing drug escape and activating cell death cascades. The review aims to offer theoretical insights for optimizing tumor drug delivery efficiency and achieving precise lysosome-mediated tumor cell death.\n\nID: 42242586\nTitle: Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.\nAbstract: Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits FIG4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.\n\nID: 42236747\nTitle: Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.\nAbstract: Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.\n\nID: 42215790\nTitle: The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.\nAbstract: Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in\u00a0amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role\u00a0of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age\u2011dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin\u20113 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery\u00a0to damaged lysosomes. Notably, mutant microglia accumulate GTP\u2011bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.\n\nID: 42183611\nTitle: Mammalian lysophagy: mechanisms and pathophysiological implications.\nAbstract: Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.Abbreviations: ALR, autophagic lysosome reformation; ALS, amyotrophic lateral sclerosis; ATG8, mammalian Atg8-family protein; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; LAMPs, lysosome associated membrane proteins; LIR, LC3-interacting region; LLOMe, L-leucyl-L-leucine methyl ester; LMP, lysosomal membrane permeabilization; PITT, phosphoinositide-initiated membrane tethering and lipid transport; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns4P, phosphatidylinositol-4-phosphate; ROS, reactive oxygen species; V-ATPase, vacuolar-type H+ -ATPase.\n\nID: 42178909\nTitle: Membrane ATG8ylation in secretory autophagy.\nAbstract: Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: A\u03b2, amyloid-\u03b2; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.\n\nID: 42155171\nTitle: Targeting lysosomal dysfunction with small-molecule TRPML1 ligands: Therapeutic opportunities in lysosomal storage disorders, neurodegeneration and beyond.\nAbstract: TRPML1, a lysosomal Ca2+ channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.\n\nID: 42143042\nTitle: VCP modulation ameliorates pathological features in C9orf72 models.\nAbstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.\n\nID: 42126673\nTitle: Dose- and time-dependent cardioprotection of liproxstatin-1 via sequential modulation of ferroptosis pathways after myocardial ischemia-reperfusion.\nAbstract: Myocardial ischemia-reperfusion (MI/R) injury significantly limits the clinical benefits of coronary reperfusion therapy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been implicated in myocardial ischemia-reperfusion (I/R) injury. Liproxstatin-1 (Lip-1) is a potent ferroptosis inhibitor, but its dynamic, dose-dependent effects on key molecular pathways and pathological hallmarks in the heart remain incompletely characterized. To systematically investigate the dose- and time-dependent cardioprotective effects of Lip-1 against myocardial I/R injury, with a focus on the NRF2/GPX4 pathway, iron deposition, and lysosomal integrity. Ninety Wistar rats were randomly allocated to 15 experimental groups (n\u2009=\u20096 per group): Normal (no surgery), Sham (thoracotomy without ischemia), I/R model, and I/R\u2009+\u2009Lip-1 treatment groups. Lip-1 was administered intravenously at doses of 1, 3, or 5\u00a0mg/kg at 0, 24, 48, and 72\u00a0h post-reperfusion initiation, with myocardial tissue and blood samples harvested 6\u00a0h after each injection. Cardiac function was assessed by echocardiography. Myocardial infarct size was determined by Evans Blue/TTC double staining. Serum levels of CK-MB and LDH were measured as markers of myocardial injury. Analyses included Western blot for NRF2 and GPX4 expression, Prussian blue staining for iron deposition quantification, and immunofluorescence for LAMP1 localization and intensity. Statistical analysis was performed using two-way ANOVA with Tukey's post hoc test for Lip-1 treatment groups, and t-tests or one-way ANOVA for model validation comparisons. Compared to Sham, I/R injury significantly decreased LVEF, increased infarct size, and elevated CK-MB and LDH levels (all P\u2009<\u20090.0001), confirming successful model establishment. It also downregulated GPX4 expression, induced severe iron deposition, and reduced LAMP1 levels, while triggering an adaptive upregulation of NRF2. Lip-1 treatment produced dose- and time-dependent protection across all measured endpoints. It improved cardiac function, reduced infarct size, and attenuated CK-MB and LDH release, with significant dose\u00d7time interactions for infarct size (F(6,60)\u2009=\u20098.338, P\u2009<\u20090.0001), CK-MB (F(6,60)\u2009=\u20096.467, P\u2009<\u20090.0001), and LDH (F(6,60)\u2009=\u20099.021, P\u2009<\u20090.0001). It dynamically modulated the NRF2/GPX4 axis, with peak GPX4 expression observed following the 48-hour administration (sampled at 54\u00a0h post-reperfusion). Lip-1 progressively reduced iron deposition, with maximal effect observed after the 72-hour administration (sampled at 78\u00a0h post-reperfusion), and rescued LAMP1 downregulation in later sampling points. Statistical analysis revealed significant dose\u00d7time interactions for NRF2 (F(6,60)\u2009=\u2009200.8, p\u2009<\u20090.0001), GPX4 (F(6,60)\u2009=\u200934.84, p\u2009<\u20090.0001), and iron deposition. High-dose Lip-1 (5\u00a0mg/kg) demonstrated superior and sustained efficacy across all parameters. Lip-1 confers multi-faceted cardioprotection against I/R injury through sequential mechanisms involving early potentiation of the NRF2/GPX4 antioxidant defense, progressive attenuation of pathological iron accumulation, and restoration of lysosomal membrane integrity. The strict dose and temporal dependency of these effects provide critical insights for optimizing ferroptosis-targeted therapeutic strategies in ischemic heart disease.\n\nID: 42094412\nTitle: TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.\nAbstract: TMEM106B is a lysosomal membrane protein and major genetic modifier of multiple neurodegenerative diseases, including frontotemporal lobar degeneration, Alzheimer's disease, and amyotrophic lateral sclerosis. Proteolytically generated C-terminal fragments of TMEM106B assemble into amyloid fibrils that accumulate in the brains of individuals with neurodegenerative disease and in cognitively normal aged adults, yet how these fibrils produce neuronal dysfunction has remained unclear. Here, we show that cytosolic and lysosome-directed TMEM106B C-terminal fragments (CTF and gCTF) form detergent-insoluble amyloid aggregates, drive redistribution of endogenous TDP-43 from the nucleus to the cytoplasm, and accelerate neuronal death. Unbiased proximity proteomics identified the inner nuclear membrane LAP1-TorsinA axis as a fragment-specific interactome, and co-immunoprecipitation confirmed a direct physical interaction between gCTF and LAP1 that was not observed with full-length TMEM106B. Fragment expression disrupted Lamin B1 organization, mislocalized the nuclear import machinery KPNB1 and RanGAP1, and impaired importin-dependent nuclear transport in primary cortical neurons. Critically, neurons harboring endogenous TMEM106B fibrillar pathology in aged human frontal cortex exhibited the same phenotypes, namely disrupted Lamin B1 and LAP1 localization and cytoplasmic redistribution of TDP-43, whereas fibril-negative neurons from the same cases and younger control tissue retained intact nuclear envelope organization. These findings define TMEM106B proteinopathy as an upstream driver of nuclear envelope disruption and nucleocytoplasmic transport failure, linking a widespread feature of brain aging to a central mechanism of neurodegeneration.\n\nID: 42070757\nTitle: Organelle-orchestrated cGAS-STING signaling and its role in neurodegeneration.\nAbstract: The cGAS-STING signaling pathway serves as a central signalling axis of the innate immune system, and its aberrant activation plays a pivotal role in inflammatory responses. Recent studies have demonstrated that its regulation depends not only on individual organelles but also on a coordinated interorganelle network. This review systematically analyze how mitochondria, centrosomes, the endoplasmic reticulum (ER), membrane contact sites (MCSs), the Golgi apparatus, endosomes, and lysosomes collectively orchestrate cGAS-STING signaling. Mitochondria initiate signaling by releasing mitochondrial DNA; centrosomes serve as platforms for double-stranded DNA accumulation to potentiate cGAS activation; the ER anchors STING in a calcium homeostasis-dependent manner; mitochondrial-associated ER membranes (MAMs) integrate calcium and lipid signaling as regulatory checkpoints governing STING trafficking to the Golgi apparatus; the Golgi amplifies downstream signaling through site-specific post-translational modifications of STING; finally, the endosome-lysosome system, together with ER-lysosome MCSs, acts as a coordinated hub for STING sorting, lysosomal degradation and signal termination. Consequently, disruption of organelle homeostasis leads to persistent STING activation. In neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and Huntington's disease, organelle dysfunction resulting from calcium overload, impaired organelle clearance, proteolytic cleavage of tethering proteins or multi-source attacks drives aberrant STING signaling. Sustained STING activity exacerbates pathological cascades such as protein misfolding, chronic neuroinflammation, and progressive neuronal loss. Therefore, therapeutic strategies targeting key regulatory nodes of the STING pathway, from upstream organelle repair to direct pharmacological inhibition, offer significant potential to mitigate disease-associated pathological progression and constitute a promising foundation for precision therapeutics in neurodegenerative disorders.\n\nID: 42034786\nTitle: SASP-driven vascular aging: unraveling the transcriptional nexus in endothelial senescence and cardiovascular disease.\nAbstract: Endothelial cell senescence represents a critical mechanistic driver in the initiation and progression of cardiovascular diseases. Senescent endothelial cells exhibit characteristic features, including cell cycle arrest-mediated primarily through the p53/p21 and p16 pathways-morphological transformations such as increased cell volume, elevated caveolin-1 expression, and loss of LaminB1, as well as activation of the senescence-associated secretory phenotype (SASP). The SASP facilitates the secretion of numerous inflammatory cytokines and chemokines, thereby fostering a state of chronic inflammation and contributing to tissue dysfunction. Key molecular regulators of endothelial senescence include transcription factors such as NF-\u03baB and p53, along with the p38 MAPK signaling pathway, which collectively modulate inflammatory responses, cell cycle progression, and stress adaptation. This review offers a comprehensive and integrative perspective on endothelial senescence as a central element in cardiovascular pathophysiology. Its novelty stems from a systematic synthesis of classical pathways, including p53/p21 and p16, with more recently implicated players such as mammalian target of rapamycin (mTOR) signaling and associated microRNAs (miRNAs), accompanied by a focused examination of the SASP as a core pathological mechanism in chronic inflammation and vascular impairment. Moving beyond singular pathways, this work constructs a multidimensional framework that integrates cell cycle arrest, morphological changes, SASP activation, and transcriptional regulation to delineate a cohesive pathological sequence through which endothelial senescence promotes cardiovascular disease.\n\nID: 42008552\nTitle: Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.\nAbstract: Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.\n\nID: 42004237\nTitle: Phosphatidylethanolamine Alleviates Osteoarthritis Progression by Inhibiting Oxidative Stress-Induced Chondrocyte Ferroptosis in a Lysosomal-Dependent Manner.\nAbstract: Lysosomal dysfunction and chondrocyte ferroptosis are pivotal drivers of osteoarthritis (OA) pathogenesis, yet their interlinked molecular mechanisms remain poorly defined. This study investigates the associations between lysosomal dysfunctions and ferroptosis in OA chondrocytes, aiming to identify actionable therapeutic targets. Human OA cartilage samples were categorized into intact and damaged groups based on structural integrity. Lysosomal fractions were isolated from both groups for comparative lipidomic profiling and functional assays. A rat OA model was established via anterior cruciate ligament transection, followed by histopathological evaluation using hematoxylin-eosin (HE) staining, Safranin-O Fast Green scoring, and immunohistochemical analysis to quantify cartilage repair and degeneration. The damaged groups displayed significantly increased lysosomal membrane permeability (LMP) and ferroptosis activation compared to intact groups. Lysosomal lipidomics revealed oxidative stress-induced down-regulation of phosphatidylethanolamine (PE), a key membrane-stabilizing phospholipid, in chondrocytes. Functional studies demonstrated that PE supplementation rescued chondrocyte viability (CCK-8 assay) and attenuated LMP-driven ferroptosis by restoring lysosomal integrity and suppressing lipid peroxidation. In vivo, intra-articular PE administration markedly reduced OA progression, as evidenced by improved cartilage histology scores, and downregulated ferroptosis markers. PE supplementation restores lysosomal PE levels, reduces LMP, and alleviates ferroptotic phenotypes in preclinical models, suggesting therapeutic potential. These findings significantly increase our understanding of the pathogenesis of OA and reveal potential therapeutic targets for its management.\n\nID: 41980172\nTitle: Polystyrene Microplastics Induced Hepatocytes Pyroptosis, Apoptosis and Ferroptosis via GSDMD-N-Mediated Mitochondrial Damage.\nAbstract: Microplastics (MPs), as emerging food contaminants, have been established to exert adverse effects on the liver. However, the precise toxicological mechanisms remain elusive. Our results demonstrated that MPs triggered mitochondrial dysfunction and mitochondrial ROS (mtROS) accumulation, which subsequently activated NLRP3/caspase-1/GSDMD-N-dependent pyroptosis in hepatocytes. Notably, beyond its canonical translocation to the plasma membrane, GSDMD-N was observed to form pores on the mitochondrial outer membrane, exacerbating mitochondrial damage. The mitochondrial GSDMD-N pores amplified mtROS overproduction, triggering lysosomal membrane permeabilization (LMP) and facilitating lysosomal iron efflux, which ultimately initiated ferroptosis. Concurrently, mitochondrial GSDMD-N mediated mitochondrial intrinsic apoptosis by promoting cytochrome c release and caspase-3 activation. Collectively, our findings revealed that MPs induced GSDMD-N activation and its mitochondrial translocation, which in turn initiated pyroptosis, ferroptosis, and apoptosis in hepatocytes. This study provided novel mechanistic insights into MPs-induced hepatotoxicity, identifying GSDMD-N as a potential central hub coordinating multiple cell death modalities.\n\nID: 41975595\nTitle: Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.\nAbstract: Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.\n\nID: 41968679\nTitle: Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.\nAbstract: Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in Pharmacological Research, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.\n\nID: 41919495\nTitle: Lysosomal homeostasis at the crossroads of neurodegeneration.\nAbstract: Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.\n\nID: 42494247\nTitle: Shikonin Alleviated Epithelial Responses in a Lipopolysaccharide/Tumor Necrosis Factor Alpha-induced Ulcerative Colitis-like Condition in Caco-2/HT-29 Co-cultured Cells by Modulating the MAPK/NLRP3/Nuclear Factor Kappa B Pathways.\nAbstract: \n\nID: 42494065\nTitle: IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.\nAbstract: Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and \u03b3\u03b4 T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3\u03b2-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.\n\nID: 42492606\nTitle: Targeting the MAPK/ERK Signaling Pathway: Mechanistic Analysis of Pexidartinib in Overcoming Adriamycin Resistance in Breast Cancer.\nAbstract: Breast cancer severely threatens women's health, adriamycin (Doxorubicin), as the first-line chemotherapy drug for breast cancer, has a serious problem of drug resistance, which severely restricts the prognosis of patients. No effective therapies are available for drug-resistant breast cancer, urging the development of novel strategies to overcome drug resistance. This study integrated transcriptomics and explored the mechanism of pexidartinib against MCF-7/ADR tumors via in vitro and in vivo experiments including fluorescence staining, flow cytometry and western blot. The CSF1R inhibitor pexidartinib potently inhibited adriamycin-resistant MCF-7/ADR cells with a much lower IC50 than parental cells. MAPK pathway enrichment was identified in drug resistance. Pexidartinib exerted multi-target synergy: suppressing MAPK/ERK and PI3K/AKT/mTOR pathways, blocking P-gp drug efflux, inducing ferroptosis and apoptosis, and inhibiting proliferation, migration and invasion. It also restrained xenograft growth, regulated related proteins and promoted tumor necrosis in nude mice. exidartinib overcomes adriamycin resistance in breast cancer through multi-target effects, providing a basis for clinical trials.\n\nID: 42491232\nTitle: Autophagy as a multi-scale architect of fungal development and pathogenicity: membrane dynamics, multilayer regulation, and cell wall integrity crosstalk.\nAbstract: Autophagy is a conserved membrane-trafficking pathway traditionally viewed as a nonspecific nutrient recycling mechanism. However, recent advances across diverse fungal systems, from plant pathogens to human opportunistic fungi and entomopathogenic species, have revealed autophagy as a central regulatory hub that orchestrates fungal development, virulence, and host interaction at multiple biological scales. This review provides a comprehensive and critical synthesis of these emerging insights. At the nanoscale, the discussion explores how autophagosome biogenesis depends on the spatially precise delivery of PtdIns4P by oxysterol-binding proteins, the dual function of the TRAPPIII vesicle-tethering complex, and the retromer-mediated sorting of vacuolar proteases. At the organelle level, the interplay between selective autophagy (mitophagy, lipophagy, pexophagy) and a newly discovered layer of epitranscriptomic, transcriptional, and post-translational regulation, comprising m5C RNA methylation of core ATG transcripts, FOX transcription-factor-driven gene activation, and nuclear acetylation of Atg8, respectively, is examined. At the macroscale, the review highlights how autophagy-dependent cell death and ferroptosis cooperate to drive appressorium maturation in Magnaporthe oryzae, and presents direct biochemical evidence for crosstalk between the cell wall integrity MAPK cascade and the autophagy machinery, a paradigm that challenges the long-standing view of these pathways as parallel systems. Further discussion addresses how autophagy deficiency triggers Mincle-dependent host immunity in Cryptococcus neoformans and how entomopathogenic Cordyceps militaris co-opts autophagy for fruiting body morphogenesis. We emphasize that the direct biochemical evidence for several of these mechanisms, notably CWI-MAPK/Atg4 crosstalk and autophagy-ferroptosis coupling, currently derives largely from Magnaporthe oryzae, and we distinguish such established mechanisms from cross-species extrapolations throughout. Finally, Atg4 inhibitors are evaluated as a promising class of broad-spectrum antifungal agents, and key directions for future research, including spatiotemporal imaging, multi-omics validation, and translational antifungal strategies, are identified.\n\nID: 42491041\nTitle: Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.\nAbstract: Histone lactylation is an emerging epigenetic modification that covalently links the glycolytic metabolite lactate to histones, thereby establishing a direct link between cellular metabolic status and gene transcription programs. Recent studies have shown that this modification plays a key role in regulating cellular sensitivity to ferroptosis, forming a novel regulatory axis of \"glycolysis-lactylation-ferroptosis.\" This article systematically reviews the biological functions of histone lactylation in the nervous system, with a focus on elucidating how it participates in the pathological processes of various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral stroke, and amyotrophic lateral sclerosis (ALS), by regulating the expression of ferroptosis-related genes. The article integrates the latest research on molecular mechanisms, explores the value of this regulatory axis as a potential biomarker for disease diagnosis and a therapeutic target, and provides an outlook on future research directions in this field.\n\nID: 42488926\nTitle: Integrative Transcriptomic and Genetic Analysis Prioritizes SLC1A5 as a Programmed Cell Death-Associated Candidate Risk Gene in Vitiligo.\nAbstract: Programmed cell death (PCD) has been implicated in various autoimmune disorders, but its role in vitiligo remains poorly understood. This study aimed to identify PCD-related genes and elucidate their potential contribution to vitiligo pathogenesis through integrative bioinformatics analysis. Three GEO datasets (GSE65127, GSE53146, GSE75819) were merged to obtain a combined cohort of 40 controls and 30 vitiligo samples. Differentially expressed genes (DEGs) were identified using limma. GSVA was applied to assess 11 PCD pathways. Summary-data-based Mendelian randomization (SMR) and HEIDI testing integrated eQTL data with vitiligo to pinpoint causal genes. Bayesian colocalization and immune infiltration analyses were further performed. A total of 922 DEGs were identified, with pyroptosis and cuproptosis signatures upregulated in vitiligo whereas overall autophagy- and lysosome-dependent cell death-related gene expression was decreased. In contrast, pathway-level GSVA using a broader autophagy-related gene set indicated upregulated autophagy signaling, highlighting the context dependence of autophagy-related signatures. Overlapping DEGs with PCD gene sets yielded 75 differentially expressed PCD-related genes. SMR analysis prioritized 602 genes associated with vitiligo risk, and intersection with PCD genes highlighted PARK7 and SLC1A5 as key candidates. Bayesian colocalization analysis provided strong genetic support for SLC1A5 as a candidate gene, with lead SNP rs8105903 showing consistent eQTL and GWAS signals. GSVA revealed downregulated melanogenesis and tyrosine metabolism alongside upregulated autophagy and NOD-like receptor signaling in vitiligo. Single-gene enrichment linked SLC1A5 to glycosphingolipid biosynthesis and melanogenesis. Immune infiltration analysis showed elevated aDC, T helper, and Th2 cells but reduced NK CD56bright cells in vitiligo. SLC1A5 was significantly downregulated in vitiligo samples and demonstrated moderate diagnostic value. This study identifies SLC1A5 as a genetically anchored PCD-associated gene potentially involved in vitiligo through metabolic reprogramming and immune modulation, and provides strong genetic evidence supporting SLC1A5 as a candidate for further mechanistic and translational investigation, while recognizing that functional studies are required before it can be considered a therapeutic target.\n\nID: 42484373\nTitle: Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese.\nAbstract: Malattia Leventinese (MAL) is an inherited macular degeneration disorder characterized by retinal drusen formation in adolescence, leading to vision loss. A mutation in the fibulin-3 gene (EFEMP1) causes MAL; however, the mechanisms underlying disease onset and drusen formation remain unclear. In this study, we generated induced pluripotent stem cell-derived retinal pigment epithelial (iPSC-RPE) cells from a patient with MAL to investigate disease mechanisms and potential therapies. MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis. Long-term culture with photoreceptor outer segments led to drusen-like deposits containing ApoE, complement components, and collagen IV accumulation, and it showed activation of matrix metalloproteinase-2 (MMP2). Untargeted lipid analysis revealed increased hexosylceramide and bis-monoacylglycerophosphate levels in MAL iPSC-RPE cells. A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels. Treatment with trehalose, a lysosome-modulating compound, increased lysosomal content and function, reducing drusen-like deposit formation, inhibiting MMP2 activation, and suppressing apoptosis. This study highlighted lysosomal dysfunction as a contributor to RPE damage, drusen-like deposit accumulation, and extracellular matrix degradation. Pharmacological restoration of lysosomal function alleviated these defects, suggesting therapeutic potential for MAL and other drusen-related diseases, including age-related macular degeneration.\n\nID: 42480904\nTitle: Niclosamide ethanolamine induces malignant phyllodes tumor cell death via mTOR-TFEB axis-mediated lysosomal biogenesis and functional uncoupling.\nAbstract: Breast malignant phyllodes tumor (MPT) is a fibroepithelial neoplasm characterized by high recurrence rates. Currently, no effective therapeutic agents are available, and surgery remains the mainstay of treatment for MPT. Niclosamide ethanolamine (NEN), an antiparasitic agent, has recently demonstrated broad-spectrum antitumor activity against various solid malignancies. This study aimed to evaluate the antitumor efficacy of NEN against MPT and elucidate the underlying molecular mechanisms. The effects of NEN on MPT cell proliferation and migration were assessed using CCK-8, wound healing, and Transwell migration assays. Ultrastructural alterations following NEN treatment were examined by transmission electron microscopy. Bioinformatics analyses, quantitative real-time PCR (qPCR), Western blotting, and immunofluorescence staining were employed to investigate the molecular mechanisms underlying NEN-mediated modulation of autophagy and lysosomal function. NEN significantly inhibited MPT cell proliferation and migration. Transmission electron microscopy revealed the accumulation of numerous autolysosomal structures in NEN-treated cells. Mechanistically, NEN suppressed mTOR phosphorylation, promoted nuclear translocation of transcription factor EB (TFEB), and induced lysosomal biogenesis. However, lysosomal function was compromised, as evidenced by elevated luminal pH, impaired cathepsin D maturation, and lysosomal membrane permeabilization, ultimately resulting in autophagic flux blockade at the degradation stage. Furthermore, lysosomal cathepsin leakage activated the mitochondrial apoptotic pathway, culminating in caspase-3-dependent apoptosis. NEN effectively kills MPT cells by inducing \"lysosomal biogenesis-function uncoupling.\" This study is the first to reveal a novel anti-MPT mechanism that targets the mTOR-TFEB-lysosome axis and disrupts lysosomal homeostasis, providing a potential drug candidate for the treatment of MPT.\n\nID: 42477452\nTitle: USP32-mediated stabilization of MAPK12 promotes lung adenocarcinoma progression by inhibiting autophagy-ferroptosis.\nAbstract: Lung adenocarcinoma (LUAD), the most common non-small cell lung cancer, often resists ferroptosis and autophagy-two tumor-suppressive, therapy-sensitive regulated cell death pathways. MAPK12 (a stress-responsive p38 MAPK kinase) boosts LUAD cell survival under oxidative stress, while USP32 (a LUAD-upregulated deubiquitinase) correlates with poor prognosis. However, the USP32-MAPK12 axis's regulatory role in LUAD ferroptosis and autophagy remains uninvestigated. USP32/MAPK12 expression in LUAD tissues/cell lines was detected via Western blotting and immunohistochemistry. Functional assays (colony formation, Transwell migration, ferroptosis/mitophagy tests) were performed after gene overexpression/knockdown. Protein interactions and ubiquitination were analyzed by co-immunoprecipitation, with in vivo validation using xenograft models. USP32 overexpression in LUAD correlated with reduced overall survival; it stabilized MAPK12 by removing K48-linked ubiquitin chains to block proteasomal degradation. USP32/MAPK12 knockdown activated autophagy/ferroptosis (elevated LC3B/ACSL4/Fe\u00b2\u207a/MDA, reduced GPX4/p62), inhibited LUAD cell proliferation/migration in vitro and tumor growth in vivo. Thus, targeting the USP32-MAPK12 axis may restore cell death sensitivity, representing a promising LUAD therapeutic strategy.\n\nID: 42477139\nTitle: Borrowed scissors for lysosome fission.\nAbstract: \n\nID: 42475369\nTitle: Chronic oral cannabidiol delays seizure onset and reduces seizure burden in a mouse model of CLN2 disease.\nAbstract: A growing body of literature describes the anti-inflammatory, neuroprotective, and anti-epileptic properties of the cannabis sativa constituent cannabidiol, suggesting that it might play a useful role in the treatment of neurodegenerative diseases. Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare pediatric neurodegenerative disorder resulting from an inherited dysfunction of the lysosome. CLN2 disease, and its representative animal models, display neuroimmune response, neuroinflammation, neurodegeneration, and epileptic seizures, and these symptoms are all touted as potential targets of cannabidiol therapeutic benefit. Here, we treated a valid model of CLN2 disease with long-term daily cannabidiol (300 mg/kg) from 1 month of age until disease end stage and evaluated epileptic seizures, lifespan, and markers of neuroimmune response. Chronic cannabidiol treatment significantly delayed or fully eliminated seizures in CLN2 model mice compared to those treated with vehicle only, and the treatment led to a non-significant extension of lifespan. These effects occurred in the absence of any therapeutic benefit to physiological markers of disease such as GFAP, CD68, and cytokine/chemokine reactivity. Taken together, we show that chronic treatment with cannabidiol confers significant anti-seizure benefit to the mouse model of CLN2 disease, and that it does not appear to do so by altering the inflammatory and neuroimmune markers traditionally used to track CLN2 disease progression.\n\nID: 42475021\nTitle: Lysosome-targeting naphthalimide-based AIEE nanoaggregates as a dual inducer of autophagy and apoptosis in cancer therapy.\nAbstract: Hallmarks of cancer remain incompletely addressed due to the lack of efficient treatments. In translational healthcare, aggregation-induced emission/aggregation-induced enhanced emission luminogens (AIE/AIEEgens), which display strong photoluminescence upon aggregation, have broad applications in therapeutic imaging, selective organelle tracking, and biomolecular detection. Carefully designed AIE/AIEEgens can generate intracellular reactive oxygen species (ROS), thereby activating apoptotic pathways. Here, we report a novel naphthalimide-based fluorophore functionalized with morpholine and 6-hydroxyquinoline units. DFT studies confirmed a donor-acceptor framework, with morpholine as the electron donor and the naphthalimide core as the electron acceptor. The synthesized AIEEgen morpholinonaphthalimide-6-hydroxyquinoline (M6HQ) efficiently targeted lysosomes and exhibited cytotoxicity in IMR-32 and MCF-7 cells. M6HQ enhanced lysosomal activity that instigated increased LC3-II/LC3-I expression and decreased p62 expression, indicating autophagic induction. Additionally, M6HQ elevated intracellular ROS production, leading to mitochondrial depolarization, cell cycle arrest, reduced cell migration, and apoptosis in IMR-32 and MCF-7 cells. Elevated levels of apoptotic marker proteins (cleaved caspase-3 and -9) in treated cells further supported the apoptotic cell death pathway. These findings highlight lysosome-targeted naphthalimide-based AIEE nanoaggregates as multifunctional theranostic agents that induce both autophagy and apoptosis, offering a dual-pathway strategy to overcome drug resistance and improve cancer therapy.\n\nID: 42471867\nTitle: Signal-driven interplay between lipid peroxidation and ferroptosis orchestrates osteoarthritis degeneration.\nAbstract: Osteoarthritis (OA) is progressively documented as a whole-joint disorder in which oxidative stress, iron dysregulation and intercellular communication together drive progressive tissue degeneration. Among the chief oxidative mechanisms, lipid peroxidation has arisen as a critical contributor to cartilage destruction and inflammatory signalling cascade. Reactive aldehydes produced during lipid peroxidation, mainly malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE), function as electrophilic mediators that change signalling pathways, extracellular matrix components and proteins, including NF-\u03baB and MAPK. Persistent oxidative stress converges on ferroptosis, an iron-dependent form of regulated cell death characterized by impaired GPX4 activity, lipid peroxide accumulation and glutathione depletion. Ferroptotic chondrocytes also amplify osteoarthritic progression by releasing matrix-degrading enzymes and inflammatory cytokines that impact neighbouring osteoclasts, osteoblasts and synoviocytes. Additionally, mechanical stress contributes to this pathological network through Piezo1/TRPV4-mediated mechanotransduction, connecting aberrant biomechanical loading to intracellular calcium imbalance, ferroptosis activation and iron accumulation. Accumulative evidence specifies that dysregulated iron homeostasis plays a dual role in OA pathogenesis, as iron overload promotes reactive oxygen species generation through Fenton chemistry, whereas iron deficiency impairs antioxidant defence and osteogenesis mechanisms. Therapeutically, biomaterial-based nano-delivery systems, antioxidant compounds, iron chelators, and ferroptosis-targeted interventions have confirmed potential in restoring redox balance and suppress OA-associated inflammation. Cerium oxide, selenium, and MnO2 nanozymes, together with smart intra-articular delivery platforms, provide targeted reactive oxygen species scavenging and improve therapeutic localization within inflamed joints. By integrating mechanotransduction, iron metabolism, ferroptosis and lipid peroxidation, inter-tissue communication into a unified mechanistic framework, this review highlights emerging diagnostic biomarkers and translational strategies for the development of disease-modifying therapies in osteoarthritis. This review proposes an effective cascade mechanism wherein mechanical and inflammatory stimulation results in iron deregulation, lipid peroxidation, ferroptosis, and finally the development of osteoarthritis. The assessment of biomarkers related to ferroptosis such as MDA, 4 HNE adducts, labile iron, and GPX4 enzymatic activities can be useful for stratifying early-stage osteoarthritis and monitoring the disease. Meanwhile, antioxidant molecules, iron chelating compounds, and nanotechnology-based intraarticular drug delivery systems represent promising strategies for the prevention of osteoarthritis development.\n\nID: 42468991\nTitle: RAS signaling at the crossroads of radioresistance and tumor immunity.\nAbstract: RAS mutations are among the most prevalent oncogenic drivers in solid tumors and are consistently associated with suboptimal responses to radiation therapy (RT). Within this family, KRAS is the dominant isoform and a central regulator of tumor stress adaptation. Increasing evidence indicates that oncogenic KRAS orchestrates radioresistance through coordinated tumor-intrinsic and microenvironmental mechanisms. Cell-intrinsically, KRAS enhances DNA damage repair, replication stress tolerance, redox buffering, and ferroptosis defense. The KRAS-NRF2-53BP1 axis exemplifies this program by accelerating non-homologous end joining and enabling rapid repair of radiation-induced DNA double-strand breaks. Concurrently, KRAS reshapes the tumor microenvironment by promoting myeloid recruitment, metabolic rewiring, impaired antigen presentation, and immune checkpoint upregulation, thereby constraining the immunogenic effects of RT. The rapid evolution of RAS-directed therapeutics, including allele-specific, ON-state, dual-state, and pan-RAS inhibitors, as well as emerging degraders and molecular reprogramming strategies, has transformed a historically \"undruggable\" target into a clinically actionable vulnerability. Preclinical evidence indicates that KRAS inhibition can restore radiosensitivity and partially recondition antitumor immunity. However, adaptive resistance frequently converges on MAPK pathway reactivation and persistent immune suppression. Integrating next-generation RAS inhibitors with RT and immune-directed therapies may therefore represent a critical strategy for achieving durable tumor control in KRAS-mutant cancers.\n\nID: 42463582\nTitle: Schizophrenia and bipolar disorder risk gene AKAP11 sustains cognitive function by regulating TFEB-mediated autophagy.\nAbstract: Schizophrenia (SCZ) and bipolar disorder (BD) share cognitive impairments and autophagy disruptions, with haploinsufficiency of AKAP11 (A-kinase anchoring protein 11) emerging as a major genetic risk factor for both disorders, though its functional role remains poorly understood. Here, we demonstrate that acute Akap11 depletion in the mouse hippocampus induces cognitive deficits, accompanied by synaptic dysfunction and autophagy dysregulation, implicating Akap11 deficiency in cognitive impairments via disrupted autophagic processes. Using in vitro models, we show that AKAP11 regulates autophagy initiation and lysosomal activity in various cell types, including neuronal cells. Mechanistically, AKAP11 deficiency results in increased phosphorylation of transcription factor EB (TFEB), impairing its nuclear translocation and downregulating its target genes critical for autophagy and lysosome biogenesis. Further, we identify an interaction between AKAP11 and PPP3CB, a phosphatase responsible for TFEB dephosphorylation, and demonstrate that inhibition of PPP3CB abrogates AKAP11-mediated TFEB dephosphorylation. Importantly, in vivo administration of a TFEB activator reduces the accumulation of autophagy substrates and mitigates cognitive impairments in Akap11-deficient mice, highlighting TFEB activation as a potential therapeutic strategy. Collectively, our findings establish AKAP11 as a key regulator of the autophagy-lysosome pathway and cognitive function, providing novel insights into the pathophysiology of SCZ and BD and suggesting therapeutic potential in targeting TFEB-mediated autophagy.\n\nID: 42463431\nTitle: VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7.\nAbstract: Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP- and LPS-induced PD mouse models and an in\u00a0vitro system utilizing astrocyte-conditioned medium to model disease-relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD-associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD-related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.\n\nID: 42461471\nTitle: METTL3-mediated N6-methyladenosine modification of circHUWE1 promotes high glucose-induced cardiomyocyte apoptosis and ferroptosis-related alterations through regulating miR-671-5p/CELF1 axis.\nAbstract: Diabetic cardiomyopathy (DCM) is a prevalent diabetes-related cardiac complication. miR-671-5p has been shown to mitigate ischemia-reperfusion-induced cardiomyocyte injury. This study investigated the role and underlying mechanisms of miR-671-5p in a DCM cell model established by exposing AC16 cardiomyocytes to high glucose (HG). The miRNA expression dataset GSE210036 from diabetic mouse hearts was analyzed. Cell injury was evaluated by assessing cell viability, apoptosis, and ferroptosis-related alterations. The expression levels and interactions of miR-671-5p, circHUWE1, and CELF1 were examined in the cell model. p38 MAPK activation was further assessed following modulation of the circHUWE1/miR-671-5p/CELF1 axis. Additionally, the m6A modification of circHUWE1 was evaluated. Bioinformatics analysis revealed decreased miR-671-5p expression in diabetic mouse hearts compared to healthy controls. HG treatment downregulated miR-671-5p expression and upregulated the levels of circHUWE1 and CELF1. circHUWE1 upregulation resulted from diminished METTL3-dependent m6A modification. Both miR-671-5p mimic and circHUWE1 knockdown attenuated HG-induced apoptosis and ferroptosis-related alterations. Mechanistically, circHUWE1 elevated CELF1 expression and subsequently activated p38 MAPK by sponging miR-671-5p. The cardioprotective effects of dexmedetomidine (Dex) are associated with the circHUWE1/miR-671-5p/CELF1 axis. In conclusion, the circHUWE1/miR-671-5p/CELF1 axis regulates HG-induced cardiomyocyte apoptosis and ferroptosis-related alterations and represents a novel mechanism underlying Dex-mediated cardioprotection.\n\nID: 42461372\nTitle: Molecular mechanisms and translational implications in apoptosis, ferroptosis, pyroptosis, and cuproptosis of spermatogonial stem cells.\nAbstract: Spermatogonial stem cells (SSCs) are essential for male fertility because they form the cellular foundation for normal spermatogenesis. Here we address the regulatory mechanisms governing cell deaths of SSCs, e.g., apoptosis, ferroptosis, pyroptosis, and cuproptosis, including transcriptional and post-transcriptional regulation, RNA-binding proteins, and epigenetic modifications (e.g., non-coding RNAs). We systematically elucidate testicular microenvironment and signaling pathways in controlling SSC deaths, including mitochondrial signaling, death receptor signaling, PI3K/AKT/mTOR, MAPK, and WNT/\u03b2-catenin pathways. We also discuss the translational applications of targeting key pathways or remodeling the microenvironment to intervene in SSC deaths. We highlight the prospects and requirements to develop the advanced technologies, e.g., the long-term in vitro human primary SSC culture systems, single cell multi-omics, novel gene editing approaches with high safety and efficiency, and translating efficacy from basic research to clinical applications. The present review aims to provide new and overall insights into better understanding the molecular mechanisms underlying cell deaths of SSCs and the pathogenesis of non-obstructive azoospermia (NOA), which could offer novel strategies for precise treatment of male infertility.\n\nID: 42459050\nTitle: Notoginsenoside R1 Alleviates Acetaminophen-Induced Liver Injury via MAPK/mTOR-Mediated Autophagy.\nAbstract: Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), yet effective therapeutic options remain limited. Although notoginsenoside R1 (NGR1) is a major bioactive saponin isolated from Panax notoginseng with established anti-inflammatory and anti-oxidant properties, its hepatoprotective potential and underlying mechanisms in APAP-induced liver injury (AILI) have not been systematically investigated. In this study, we established an AILI mouse model and evaluated the protective effects of NGR1 through biochemical assays, histopathology, Western blotting, and immunofluorescence, complemented by integrative transcriptomic, metabolomic, and gut microbiota analyses. Mechanistic involvement of the MAPK/mTOR-autophagy pathway was further validated using L-leucine as a pharmacological activator of mTOR. NGR1 markedly attenuated AILI, as reflected by reduced serum ALT/AST levels, improved hepatic histology, and increased survival in acute liver failure. NGR1 suppressed inflammatory responses by decreasing IL-1[Formula: see text], IL-6, and TNF-[Formula: see text] levels and alleviated oxidative stress by restoring GSH and SOD while reducing MPO, ROS, and MDA accumulation. Multi-omics analysis revealed significant enrichment of MAPK/mTOR signaling, autophagy, ferroptosis, and glutathione metabolism pathways. Mechanistically, NGR1 promoted autophagic flux (increased LC3-II/I, ATG5, and ATG7 with decreased p62), inhibited ferroptosis (upregulation of GPX4 and SLC7A11 with downregulation of ACSL4), and suppressed APAP-induced activation of the MAPK/mTOR pathway. Pharmacological activation of mTOR by L-leucine partly abolished the protective effects of NGR1, reversing autophagy activation and restoring inflammatory and oxidative injury. These findings collectively demonstrate that NGR1 protects against AILI by inhibiting MAPK/mTOR signaling, restoring autophagy, and suppressing ferroptosis, highlighting NGR1 as a promising therapeutic candidate for APAP-induced hepatotoxicity.\n\nID: 42453424\nTitle: PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease.\nAbstract: Aberrant metabolic alterations underlie microglial dysfunction, which plays an important role during neurodegenerative progression. However, the role of aberrant glycogen metabolism remains elusive. Here, we identified glycogen accumulation and upregulated glycogenolytic enzymes in brain microglia from patients with Alzheimer's disease (AD) and transgenic animal models. Particularly, the principal microglial glycogenolytic enzyme PYGL exhibited the most notable spatiotemporal upregulation during disease progression. Specific knockdown of microglial PYGL ameliorated neuropathological changes and cognitive deficits in AD mice. Bioinformatics analysis and experimental validation confirmed that enhancing microglial autophagic flux-dependent A\u03b2 clearance was the underlying mechanism. Furthermore, among all possible glycogenolytic pathways, PYGL downregulation primarily reduced hexosamine biosynthesis pathway activity, diminished UDP-GlcNAc and O-GlcNAcylation of the autophagy key protein SNAP29, and thereby facilitated formation of the SNARE complex, which is essential for autophagosome-lysosome fusion. These findings reveal a glycogenolysis-driven post-translational pathway regulating microglial autophagy, establishing PYGL as a therapeutic target for AD.\n\nID: 42451740\nTitle: Lysosomes in Ferroptosis: Regulatory Mechanisms and Molecular Targets.\nAbstract: Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and membrane damage, with broad relevance to human disease. Accumulating evidence suggests that ferroptosis is governed by coordinated organelle-level regulation, among which lysosomes have emerged as central hubs. By controlling endolysosomal iron processing, transport, and degradation pathways, lysosomes shape the intracellular distribution and reactivity of iron, thereby modulating iron-driven lipid peroxidation. The acidic, iron-rich microenvironment and limited local antioxidant capacity render lysosomal membranes highly susceptible to oxidative injury, positioning lysosomes as initiation and amplification sites of lipid peroxidation. Meanwhile, lysosome-dependent selective autophagy pathways actively remodel iron homeostasis, lipid metabolism, and cellular antioxidant defenses, thereby dynamically modulating ferroptotic sensitivity. Mitochondria-lysosome crosstalk further redistributes iron, reactive oxygen species, and lipid substrates, linking lysosomal activity to interorganelle control of ferroptosis. Lysosomal stress-responsive signaling also coordinates metabolic adaptation and redox control. This review summarizes and integrates current evidence on lysosome-centered mechanisms that organize iron metabolism, lipid peroxidation, selective autophagy, organelle crosstalk, and stress-responsive signaling during ferroptosis, and further discusses their disease-specific roles, therapeutic potential, and translational challenges.\n\nID: 42451124\nTitle: Neuroprotective Effects of Sorghum Polyphenol in Alzheimer's Disease: In Vitro and In Silico Analyses.\nAbstract: Accumulation of amyloid-beta (A\u03b2) senile plaques in the human brain is a major hallmark of Alzheimer's disease (AD), which manifests as progressive decline in memory and cognitive functions and currently lacks effective disease-modifying therapies. Emerging evidence demonstrates that polyphenol-rich plant foods are potential complementary therapies for AD. In this study, we investigated crude polyphenol extracts (CPEs) and purified polyphenol extracts (PPEs) from three sorghum genotypes for their ability to inhibit A\u03b242-induced toxicity in MC-65 cells. Thioflavin T fluorescence, cell viability, mitochondrial function, oxidative stress assays, and Western blotting, along with RNA sequencing and computational analyses, were used to characterise both functional and transcriptomic responses of the cells to polyphenol treatments. CPEs and PPEs inhibited A\u03b242 aggregation by 67-76% and significantly reduced A\u03b2 oligomer species. The extracts increased cell viability against A\u03b2-induced toxicity by more than 70%, decreased intracellular oxidative stress, and enhanced mitochondrial activity by over 80%. Transcriptomic profiling revealed differential modulation of genes associated with ferroptosis and MAPK/NF- \u03baB signalling pathways, indicating regulation of inflammatory and oxidative-stress responses are mechanisms underlying the observed neuroprotection. This study demonstrates that polyphenol extracts from black and red sorghum genotypes exert strong multitarget neuroprotection against A\u03b242 toxicity in MC-65 cells. These findings support further evaluation of sorghum-derived polyphenols as complementary therapeutic candidates for AD, with in vivo studies required to establish efficacy and translational potential.\n\nID: 42450688\nTitle: Post-Transcriptional Regulatory Network of Non-Coding RNAs in Yaks: Molecular Mechanisms of Hypoxia Adaptation and Productive Traits.\nAbstract: Yaks have long inhabited the Qinghai-Tibetan Plateau. This region features low-oxygen, frigid temperatures and pronounced seasonal variation in nutrient availability. They have evolved adaptive phenotypes centered on energy metabolism reprogramming, tissue structure remodeling, and stress homeostasis maintenance. In recent years, non-coding RNAs (ncRNAs) have been confirmed as an important component of the yak's post-transcriptional regulatory network. They play a key bridging role between environmental stress perception and phenotypic output through mechanisms such as influencing RNA splicing, stability, translation activity, and constructing competitive endogenous RNA (ceRNA) networks. This article systematically reviews the biogenesis pathways and core regulatory patterns of circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). It focuses on summarizing the expression profile characteristics and dynamic spatiotemporal changes of these three types of ncRNAs in physiological contexts such as muscle and fat deposition, mammary gland lactation, testicular development, and hypoxia response in the heart, lungs, and vascular system of yaks. Current research evidence indicates that the regulatory network of yaks ncRNAs shows significant convergence on multiple key signaling pathways, mainly concentrating on lipid metabolism (PPAR/AMPK), nutrition and growth signals (PI3K-Akt/MAPK/mTOR), extracellular matrix remodeling (ECM-receptor interaction, Wnt/TGF-\u03b2), and cell stress fate determination (apoptosis, oxidative stress/ferroptosis) modules. Among them, some core circRNA and lncRNA-miRNA-mRNA regulatory axes have been functionally validated in vitro. Despite the phased progress, current research on ncRNA in yaks still faces bottlenecks: the multi-omics molecular atlases (encompassing genomics, transcriptomics, proteomics, and metabolomics) of key high-altitude adaptive organs remain incomplete, analysis processes lack sufficient standardization, and most studies stay at the association network level with limited causal mechanism validation. To address these limitations, future research should focus on building a standardized evidence chain, integrating multi-omics and single-cell/spatial transcriptome technologies, and conducting mechanism verification for traits in independent populations, thereby providing a solid theoretical basis for understanding the extreme environmental adaptation mechanisms of yaks and molecular breeding improvement.\n\nID: 42449974\nTitle: Exploring the Therapeutic Potential of Ganoderic Acid A Against Inflammatory Bowel Disease Based on Network Pharmacology, Molecular Docking, and Intestinal Organoid Validation.\nAbstract: Inflammatory bowel disease (IBD) poses a significant global health burden with rising incidence, particularly in Asia. This study employed an integrative network pharmacology approach combined with molecular docking to elucidate the therapeutic mechanism of ganoderic acid A (GAA) against IBD. Potential GAA targets were retrieved from pharmacogenomic databases, while IBD-related genes were curated from OMIM and GeneCards databases. Weighted gene co-expression network analysis of IBD transcriptomic datasets (GSE38713, GSE126124) identified disease-associated modules, with the yellow module exhibiting the strongest positive correlation. Functional enrichment analyses demonstrated significant involvement of overlapping targets in lipid metabolism, the inflammatory response, and the mitogen-activated protein kinase (MAPK) signaling cascade pathway. We identified 14 IBD-GAA-ferroptosis-related genes and 54 key module genes. Intersection analysis revealed 5 overlapping targets, including tumor necrosis factor-\u03b1(TNF-\u03b1), peroxisome proliferators-activated receptor \u03b3 (PPAR\u03b3), MAPK14, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic \u03b1 (PIK3CA), and Caspase 3 (CASP3). Molecular docking confirmed high-affinity binding of GAA to these targets, with binding energies ranging from -7.3 to -10 kcal/mol. Crucially, experimental evaluation demonstrated the pivotal role of GAA in alleviating disease pathology. GAA treatment suppressed the significantly elevated levels of TNF-\u03b1 and p-MAPK14 in the organoids using a cytokine/LPS-induced IBD model. These findings collectively suggest a potential involvement of GAA in pathways associated with ferroptosis regulation, although direct experimental evidence for ferroptosis markers remains to be established. The observed multi-target effects on immune regulation and cellular proliferation/differentiation provide a foundation for further mechanistic investigation.\n\nID: 42449637\nTitle: Targeting Sirtuins in Thyroid Cancer: Mechanisms, Drug Development, and Emerging Roles in Tumor Immunity and Ferroptosis.\nAbstract: Thyroid cancer (TC) is the most common endocrine malignancy, with incidence increasing worldwide. Although most differentiated TCs have a favorable prognosis, radioiodine (RAI)-refractory differentiated thyroid cancer (DTC), BRAF inhibitor-resistant papillary thyroid cancer, and anaplastic thyroid cancer (ATC) remain major areas of unmet clinical need. The sirtuin (SIRT) family of NAD+-dependent enzymes has emerged as a multifaceted regulator of TC biology, with isoform-specific dichotomous roles: SIRT1, SIRT6, and SIRT7 act as tumor promoters through engagement of BRAF/MAPK, PI3K/AKT, epithelial-mesenchymal transition (EMT), and Hippo pathways, while SIRT3 and SIRT4 function as tumor suppressors via mitochondrial metabolic regulation. This review synthesizes recent developments that expand the therapeutic landscape: (i) the recognition that SIRT7 functions as a desuccinylase with preclinically identified oncogenic substrates, modifying KIF23 in ATC and LATS1 in PTC; (ii) the emerging roles of isoform-specific SIRT axes, including the NAMPT-SIRT1-PD-L1 axis, SIRT6-associated regulatory T-cell biology, and SIRT2 as a T-cell metabolic checkpoint, as determinants of immune microenvironment state and potential modulators of immune checkpoint inhibitor response; and (iii) the SIRT6-nuclear receptor coactivator 4 (NCOA4) ferritinophagy axis as a supported ferroptosis vulnerability in ATC, with potential but still hypothesis-generating relevance to dedifferentiated and RAI-refractory DTC. Importantly, the therapeutic logic for SIRT6 is disease-state-specific rather than contradictory: SIRT6 inhibition is rationalized in BRAF-driven aggressive PTC and DTC contexts where SIRT6 supports MAPK signaling, EMT, and ferroptosis resistance, whereas in SIRT6-high ATC, the same enzyme's NCOA4-dependent ferritinophagy activity may instead be exploited to enhance ferroptosis sensitivity. We review the current SIRT modulator pharmacological toolkit-including EX-527, OSS_128167, and emerging SIRT7-selective inhibitors-and identify the substantial clinical translation gap, with no SIRT-targeted clinical trial yet conducted in TC, despite strong preclinical rationale. We outline biomarker-stratified combination strategies with BRAF/MEK inhibitors, multikinase inhibitors, immune checkpoint inhibitors, and ferroptosis inducers, prioritizing biomarker-driven preclinical validation and, where supported by efficacy and safety data, subsequent early-phase evaluation in BRAF V600E-mutant and SIRT6-high thyroid cancer. Sirtuins thus represent a mechanistically promising and potentially biomarker-stratifiable therapeutic hypothesis for difficult-to-treat thyroid cancer; however, clinical translation remains at an early stage and requires validated biomarkers, isoform-selective compounds, and disease-specific in vivo evidence.\n\nID: 42449477\nTitle: Asprosin Protects H9C2 Cells From Ferroptosis Following Hypoxia/Reoxygenation by Promoting Mitophagy.\nAbstract: Acute myocardial infarction is a leading cause of death globally. Percutaneous coronary intervention is the primary treatment to restore blood flow to the affected myocardium, but reperfusion can cause myocardial injury, affecting the prognosis of patients with acute myocardial infarction. Asprosin (ASP) is a newly discovered adipokine whose role in myocardial protection requires further research. The GSE240847 dataset was downloaded from the GEO database, and 511 ferroptosis-related genes were collected from the FerrDb database. Gene coexpression network analysis (WGCNA) was performed to identify coexpression modules associated with Fibrillin 1 (FBN1), followed by enrichment analysis. H9C2 cells were subjected to hypoxia/reoxygenation (H/R) and pretreated with ASP at different concentrations. The effects of ASP were determined by measuring cellular reactive oxygen species (ROS), Cell Counting Kit-8 (CCK-8), and lactate dehydrogenase (LDH) levels and assessing the expression of ferroptosis-related proteins, intracellular iron content, mitophagy-related proteins, and mitochondrial membrane potential. Enrichment analysis showed Gene Ontology (GO) terms linked to GTPase signaling, chromosome behavior, and cell stability. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted mitophagy and MAPK pathways in the FBN1 module. ASP cut ROS, boosted cell viability, and raised glutathione peroxidase 4 (GPX4)/solute carrier family 7 member 11 (SLC7A11) expression, upregulating glutathione and lowering iron particles dose dependently post H/R. It also increased PINK1 and stabilized mitochondria. A mitophagy inhibitor reduced these effects. This study confirms the protective effects of ASP on myocardial cells after H/R injury and demonstrates that ASP can inhibit ferroptosis and promote mitophagy in myocardial cells during ischemia-reperfusion injury. The potential mechanism may involve ASP promoting PINK1-associated mitophagy in myocardial cells after H/R injury to inhibit ferroptosis.\n\nID: 42445556\nTitle: Ferroptosis Signature Correlates with Ovarian Cancer Prognosis and Chemotherapy Response.\nAbstract: Ovarian cancer is a leading cause of gynecological cancer mortality, with late diagnosis, high recurrence and chemotherapy resistance closely linked to the tumor microenvironment (TME). Ferroptosis, an iron-dependent regulated cell death, is a promising therapeutic target, but its role in ovarian cancer TME remodeling and treatment resistance remains unclear. We integrated bulk transcriptome and single-cell multi-omics datasets from ovarian cancer patient cohorts. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were applied to develop and externally validate a ferroptosis-related risk signature (FRS) across independent cohorts including TCGA-OV and GSE14764. We systematically analyzed correlations between FRS and clinical outcomes, TME immune landscape, somatic genomic aberrations, as well as computationally predicted chemotherapeutic susceptibility. Subsequent in vitro assays using two ovarian cancer cell lines (SKOV3 and Caov-3) were conducted to preliminarily explore the combined anti-tumor activity of Erastin and paclitaxel, alongside underlying molecular associations. We established a 17\u2011gene\u2011based Ferroptosis Sensitivity Score (FRS), with a mean index of 0.741 across the cohort. FRS effectively stratified patients into high/low-risk groups with significant survival differences; high-risk patients had a suppressive immune TME, enriched tumor-promoting pathways and distinct genomic alterations. FRS was an independent prognostic biomarker, and a nomogram integrating FRS and clinical features improved survival prediction. In vitro, Erastin dose-dependently upregulated ferroptosis-associated proteins in SKOV3 and Caov-3 cells; combining Erastin with paclitaxel alleviated paclitaxel resistance, induced apoptosis, and transcriptomic analysis showed DEGs enriched in cell division, cell cycle, MAPK and lipid metabolism pathways, confirming their synergistic anti-tumor effect via regulating ferroptosis, apoptosis and multiple signaling pathways. This work constructs a ferroptosis-derived risk signature with prognostic and chemoresponse predictive value for ovarian cancer, supported by multi-omics cohort analysis. Preliminary in vitro data from two ovarian cancer cell lines (SKOV3 and Caov-3) imply combinatorial Erastin-paclitaxel treatment may exert synergistic anti-tumor effects and alleviate paclitaxel resistance. Our findings offer preliminary clues correlating ferroptosis with TME remodeling and lay a preliminary theoretical foundation for exploring combinatorial regimens to counter chemoresistance in ovarian cancer.\n\nID: 42443900\nTitle: Dual targeting of interlocked PTK2B and MAPK signaling triggers synergistic ferroptosis via autophagic flux disruption in BRAFV600E glioma.\nAbstract: BRAFV600E mutation is one of the most common oncogenic drivers in gliomas, sharing the highest incidence in pediatric low-grade gliomas (~\u200920%) and being frequently associated with poor prognosis. Although combination therapies targeting both BRAFV600E and downstream MAPK signaling have been developed, their efficacy is substantially limited by acquired drug resistance. Consequently, identifying the underlying mechanisms of resistance and novel therapeutic vulnerabilities remains an urgent need. Using patient gene expression profiles, immunohistochemistry on glioma samples, glioma cell lines, and a Drosophila glioma model, we identified Protein Tyrosine Kinase 2 Beta (PTK2B) as a druggable vulnerability in BRAFV600E glioma. Loss-of-function studies were achieved by PTK2B knockdown in DBTRG-05MG cells and Fak knockout in Drosophila, assessing effects on tumor survival/proliferation. The underlying signaling mechanisms were investigated using RNA sequencing, proteomics and a suite of assays (e.g., Western blot, immunofluorescence, flow cytometry). Finally, the reciprocal compensatory mechanism between PTK2B and MAPK signaling was established in both cellular and Drosophila models, and the synergistic effect of their co-inhibition was validated in DBTRG-05MG and AM-38 cells. PTK2B and its Drosophila orthologue Focal adhesion kinase (Fak) are highly expressed in BRAFV600E/dRafGOF glioma, and their inhibition significantly suppresses tumor growth. Our studies revealed that PTK2B knockdown triggers potent ferroptosis in glioma cells through endoplasmic reticulum stress-induced autophagic flux disruption, a mechanism which is partially overlapped with the cell death induced by MAPK signaling inhibition. We uncovered the interlocking mechanism between highly expressed PTK2B and hyperactive MAPK signaling in BRAFV600E glioma, wherein suppression of either one prompts compensatory upregulation of the other, thereby attenuating tumor cell death under the stress. Simultaneous inhibition of PTK2B and MAPK signaling achieves strong synergistic anti-tumor effect, highlighting the therapeutic promise of this combination strategy. Our findings establish PTK2B as a critical regulator and co-targetable vulnerability in BRAFV600E glioma. We delineate a novel interlocking mechanism wherein PTK2B and MAPK engage in reciprocal negative feedback regulation, enabling adaptive resistance. This work provides a compelling mechanistic rationale for co-targeting PTK2B and MAPK to disrupt this survival axis and overcome therapeutic resistance.\n\nID: 42442861\nTitle: Sensitive detection of lysosomal membrane permeabilization using the galectin puncta assay.\nAbstract: The Lysosomal Galectin Puncta Assay is a microscopy-based technique able to detect even minor lysosomal leakage with high sensitivity. This protocol describes the detection of galectin puncta as markers of lysosomal membrane permeabilization, a process that relies on the high-affinity binding of the cytosolic galectins to the luminal glycans exposed on damaged lysosomes. Compared to traditional methods, the Galectin Puncta Assay offers high sensitivity, detects subtle lysosomal leakage, and enables analysis at single-lysosome level. Here, we provide a step-by-step protocol for this assay, covering sample preparation, immunostaining, imaging and image quantification.\n\nID: 42438288\nTitle: Ginsenoside Rg3 in Cancer Therapy: Pharmacokinetics, Molecular Mechanisms, and Synergistic Combinations.\nAbstract: Ginsenoside Rg3, a rare protopanaxadiol-type saponin enriched during the heat processing of Panax ginseng, has attracted increasing attention as a multitarget anticancer agent. This systematic review examines the anticancer potential of Rg3 through comprehensive searches of the PubMed and Web of Science databases, with a focus on peer-reviewed preclinical and clinical studies. The therapeutic efficacy of Rg3 is critically influenced by its stereochemical configuration, concentration-dependent bidirectional regulation, and pharmacokinetic constraints, including poor oral bioavailability, rapid clearance, and gut microbiota-mediated metabolism. Nanocarrier-based and targeted delivery systems have substantially improved its pharmacokinetic profile and tumor accumulation, supporting its further development for anticancer applications. Within this pharmacological context, Rg3 exhibits broad-spectrum anticancer activity across multiple solid tumors, including hepatocellular carcinoma, melanoma, lung, ovarian, breast, colon, gastric, and prostate cancers, as well as osteosarcoma, renal cancer, lung adenocarcinoma, glioblastoma, gallbladder, nasopharyngeal, cervical, and pancreatic cancers, and the hematological malignancy multiple myeloma. Mechanistically, Rg3 suppresses cancer progression through coordinated regulation of proliferation, apoptosis, autophagy, ferroptosis, angiogenesis, epithelial-mesenchymal transition, cancer stemness, immune evasion, and redox homeostasis, primarily involving the PI3K/AKT/mTOR, NF-[Formula: see text]B, MAPK, Wnt/[Formula: see text]-catenin, EGFR, and p53 pathways. These effects reflect transferable network-level mechanisms rather than tumor type-restricted actions. Moreover, Rg3 demonstrates synergistic effects with chemotherapy, radiotherapy, targeted therapy, and immunotherapy, while reversing drug resistance and attenuating treatment-related toxicity in multiple cancer models and clinical settings. Overall, this review systematically integrates current evidence on the pharmacokinetics, anticancer spectrum, molecular mechanisms, synergistic combinations, immunomodulatory effects, and clinical applications of Rg3, providing a concise framework for the rational development of Rg3-based combination strategies in precision cancer therapy.\n\nID: 42436163\nTitle: PRMT6 acts as a pro-angiogenic factor in colorectal cancer.\nAbstract: The progression of colorectal cancer (CRC) is highly dependent on tumor angiogenesis, a process primarily regulated by hypoxia-inducible factor HIF-1\u03b1. This study focuses on the mechanistic role of protein arginine methyltransferase 6 (PRMT6) in CRC angiogenesis and reveals that PRMT6 is significantly overexpressed in CRC tissues, stabilizing HIF-1\u03b1 via the autophagy-lysosome pathway. Specifically, PRMT6 catalyzes the asymmetric dimethylation of HIF-1\u03b1 at arginine 463, which disrupts its interaction with the autophagy-related protein TAX1BP1, thereby preventing its degradation. In vivo experiments demonstrate that PRMT6 silencing reduces HIF-1\u03b1 stability, decreases vascular endothelial growth factor A (VEGFA) expression, and markedly suppresses tumor angiogenesis and growth. This study identifies the PRMT6-HIF-1\u03b1 axis as a novel therapeutic target for CRC and suggests that targeting this pathway may facilitate the development of precision anti-angiogenic therapies.\n\nID: 42430924\nTitle: Co-exposure to lead and copper induces ferroptosis-related neurotoxicity in zebrafish larvae via oxidative stress and mitochondrial dysfunction.\nAbstract: Lead (Pb) and copper (Cu) frequently co-occur in aquatic environments, yet their combined neurotoxic mechanisms remain unclear. Here, zebrafish (Danio rerio) larvae were exposed to environmentally relevant concentrations of Pb (10\u202f\u03bcg/L) and Cu (20\u202f\u03bcg/L) to assess neurobehavioral and molecular effects. Co-exposure reduced locomotor activity, altered stress-related behavioral responses, and increased developmental abnormalities. Acetylcholinesterase activity was suppressed, accompanied by elevated lipid peroxidation and disrupted antioxidant defenses. Apoptosis was activated via Bax/Bcl-2/Caspase-3 modulation, with downregulation of neurodevelopmental and neurotransmission marker genes. Ferroptosis emerged as a significant contributor to Pb\u202f+\u202fCu neurotoxicity, as indicated by dysregulation of nrf2, keap1, and gpx4. Mitochondrial dysfunction was evident through reduced ATP, impaired biogenesis, disrupted electron transport, and excessive fission. Inflammation was mediated via NF-\u03baB/p38-MAPK pathway, with upregulation of pro-inflammatory cytokines and altered anti-inflammatory markers. Western blotting confirmed activation of Nrf2/Keap1/HO-1 signaling axis, highlighting the functional role of ferroptosis in Pb- and Cu-induced neurotoxicity. Importantly, treatment with the ferroptosis inhibitor ferrostatin-1 partially alleviated oxidative damage and neurobehavioral deficits, supporting a contributory role of ferroptosis in the observed effects. Overall, these findings indicate that co-exposure to Pb and Cu induces neurotoxicity in zebrafish larvae through interconnected pathways involving oxidative stress, mitochondrial dysfunction, and ferroptosis-associated processes. This study highlights the ecological relevance of metal co-exposure and its potential risks to aquatic organisms.\n\nID: 42421041\nTitle: Advances in electroacupuncture for perioperative neurocognitive disorders: mechanisms and clinical evidence.\nAbstract: Perioperative neurocognitive disorders (PND), including postoperative delirium, delayed neurocognitive recovery, and postoperative cognitive dysfunction, are common complications in older surgical patients and are associated with impaired recovery, reduced quality of life, and increased postoperative morbidity. Current management remains largely supportive and preventive, and effective targeted therapies are still lacking. Electroacupuncture (EA), as a minimally invasive neuromodulatory intervention, has attracted increasing attention because of its potential multi-target regulatory effects. This review summarizes current mechanistic and clinical evidence regarding EA for PND. Preclinical studies suggest that EA may modulate several interacting pathological processes, including neuroinflammation, oxidative stress, autophagy dysfunction, ferroptosis, mitochondrial injury, microbiota-gut-brain axis dysregulation, and hippocampal synaptic plasticity. Recent PND/POCD animal studies further support EA-related regulation of NLRP3 inflammasome activation, cGAS-STING signaling, SIRT1/NRF2/GPX4-mediated ferroptosis, AMPK/SIRT1/FOXO1/PINK1/Parkin-related autophagy pathways, and MAPK-related synaptic plasticity. Clinical studies and meta-analyses suggest that EA and related acupoint-based electrical stimulation techniques may reduce early postoperative cognitive decline and improve short-term cognitive outcomes in older surgical patients. However, the overall evidence remains limited by heterogeneous stimulation protocols, variable acupoint prescriptions, incomplete blinding, short follow-up, and reliance on cognitive screening scales. Several proposed mechanisms are still partly inferred from non-PND models. Future studies should use standardized EA protocols, clinically relevant PND models, dynamic mechanistic assessments, and adequately powered sham-controlled trials to clarify the therapeutic role of EA in PND.\n\nID: 42496855\nTitle: In Vivo Longitudinal Mapping of Brain Iron Accumulation After Pilocarpine-Induced Status Epilepticus.\nAbstract: Iron accumulations have been identified in resected tissue from patients with refractory temporal lobe epilepsy. These deposits are linked to ferroptosis, a form of nonapoptotic cell death in which iron catalyzes the formation of reactive oxygen species, leading to lipid peroxidation. Experimentally, this process has recently been associated with seizures based on the increased levels of specific markers (4-hydroxynonenal and malondialdehyde) in the brain and plasma. Quantitative susceptibility mapping (QSM) offers an opportunity to detect the iron accumulations in vivo. In this study, we investigated how pilocarpine-induced status epilepticus contributes to the generation of iron deposits in diverse cerebral regions and whether QSM can detect these deposits longitudinally. We scanned 14 animals (n\u2009=\u200910 experimental and n\u2009=\u20094 control) at five different time points (pre-status epilepticus induction and 1, 7, 14, 21\u00a0days postinduction) using QSM. We identified iron deposits in the caudate putamen, hippocampus, thalamus, and primary somatosensory cortex of experimental animals, which is consistent with histological findings. The initial size of the hippocampal iron deposits significantly increased over the following weeks. None of these effects was observed in the control animals. The presence of cerebral iron depositions in epilepsy-related brain structures suggests that they could be involved in the onset, development, and progression of spontaneous recurrent seizures. Furthermore, noninvasive, longitudinal in vivo mapping of brain iron deposits could be a potential imaging marker in neurological disorders such as epilepsy. Future experiments will be required to determine the origin of the iron and avoid its progressive accumulation.\n\nID: 42496814\nTitle: Lapatinib Induces Ferroptosis in Cardiomyocytes by Regulating ATF4/GPX4.\nAbstract: The TKI-targeted agent lapatinib has been applied in clinical oncology for the management of multiple malignancies. Nonetheless, its therapeutic benefit is restricted by cardiotoxic effects that endanger patient survival, and the underlying molecular basis remains unclear.\u00a0The GSE146096 dataset containing transcriptomic profiles of lapatinib-exposed human cardiomyocytes was analyzed to identify ferroptosis-related differentially expressed genes (DEGs). Protein expression of selected targets was subsequently confirmed by Western Blot. Reactive oxygen species (ROS) accumulation, Fe\u00b2\u207a levels, and mitochondrial membrane potential in AC16 cells exposed to lapatinib were examined using confocal microscopy. A microplate reader was employed to quantify alterations in malondialdehyde (MDA) and glutathione (GSH) levels in cardiomyocytes.\u00a0Eight ferroptosis-associated genes were identified in lapatinib-treated cardiomyocytes, including the canonical regulator GPX4. siRNA interference and Western Blot analyses demonstrated marked induction of ATF4 expression and significant suppression of GPX4 expression following lapatinib exposure in AC16 cells. CCK-8 assays indicated dose-dependent cytotoxicity. Confocal microscopy and transmission electron microscopy (TEM) revealed altered mitochondrial morphology accompanied by a reduction in mitochondrial membrane potential. Intracellular MDA levels increased substantially, whereas GSH levels declined, indicating lipid peroxidation and subsequent ferroptosis. Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or silencing of ATF4 expression effectively attenuated lapatinib-induced cytotoxicity.\u00a0Lapatinib enhances ATF4 expression in cardiomyocytes, suppresses GPX4, triggers lipid peroxidation, induces ferroptosis, and thereby contributes to cardiotoxicity.\n\nID: 42496762\nTitle: Atranorin suppresses the LUCAT1/STAT3 axis to induce ferroptotic cell death in ovarian cancer.\nAbstract: Ovarian cancer remains the most lethal gynecological malignancy and represents a major cause of cancer-related mortality among women worldwide. Despite advances in therapeutic strategies, treatment efficacy is frequently limited by systemic toxicity, chemoresistance, and disease recurrence, highlighting the urgent need for novel, mechanism-based targeted therapies with improved safety profiles. In the present study, we investigated the anti-cancer activity of atranorin (ATR), a naturally derived small-molecule compound, with a particular focus on its ability to induce ferroptosis by modulation of the LUCAT1/STAT3 signaling axis. Human ovarian cancer cell lines (OVCAR-3 and SKOV-3) and normal ovarian surface epithelial (OSE) cells were employed to evaluate cytotoxic selectivity and mechanistic effects. ATR selectively inhibited proliferation of ovarian cancer cells while exerting minimal cytotoxicity toward normal OSE cells. Mechanistic analyses demonstrated that ATR significantly suppressed LUCAT1 and STAT3 expression at both mRNA and protein levels, as confirmed by qRT-PCR and Western blotting. Concomitantly, ATR upregulated ferroptosis-related genes and proteins. Biochemical assessments revealed increased intracellular reactive oxygen species (ROS), elevated malondialdehyde (MDA) and iron accumulation, and depletion of glutathione (GSH), collectively indicating activation of ferroptotic cell death. Furthermore, ATR significantly impaired migratory and invasive capacities of ovarian cancer cells. Collectively, our findings identify ATR as a compound capable of inducing biochemical features consistent with ferroptosis in ovarian cancer through suppression of the LUCAT1/STAT3 axis. These results uncover a previously uncharacterized mechanistic pathway underlying ATR-mediated anti-tumor effect and support its potential development as a targeted therapeutic candidate for ovarian cancer management.\n\nID: 42495964\nTitle: Targeting NAE1 suppresses osteoclastogenesis via dual regulation of ferritinophagy and ACSL3-mediated ferroptosis.\nAbstract: Neddylation regulates diverse cellular processes, yet its role in osteoclast-mediated bone resorption is poorly understood. Here, we identify NAE1 (NEDD8 activating enzyme E1 subunit 1)-mediated neddylation as a critical regulator of postmenopausal osteoporosis and osteoclast differentiation through two distinct regulatory mechanisms. Pharmacological inhibition of Nae1 or myeloid-specific genetic ablation of Nae1 attenuated osteoclastogenesis in vitro and ameliorated ovariectomy (OVX)-induced osteoporosis in vivo without impairing osteoblast function. Mechanistically, Nae1 depletion disrupted intracellular iron metabolism, thereby suppressing ferritinophagy initiation in osteoclast precursors. Concurrently, integrated transcriptomics and affinity purification-mass spectrometry revealed ACSL3 as a direct neddylation substrate. Nae1-mediated neddylation modulates monounsaturated fatty acid (MUFA) biosynthesis, regulating the sensitivity of bone marrow-derived macrophages (BMDMs) to ferroptosis. This dual regulatory mechanism coordinately governs ferritinophagy initiation in iron metabolism and the sensitivity to ferroptosis mediated by ACSL3 neddylation, thereby critically influencing osteoclastogenesis. Clinically, serum MUFA levels positively correlated with bone mineral density (r\u2009=\u20090.329, p\u2009<\u20090.05). These findings support MLN4924, a clinical-stage NAE inhibitor, as a potential therapeutic strategy for osteoporosis and define an Nae1-ACSL3-MUFA-ferroptosis axis regulating osteoclast metabolism.Abbreviations: 4-HNE: 4-hydroxynonenal; ACP5/TRAP: acid phosphatase, tartrate resistant; ACSL3: acyl-CoA synthetase long chain family member 3; ACSL4: acyl-CoA synthetase long chain family member 4; BGLAP/OCN: bone gamma-carboxyglutamate protein; BMD: bone mineral density; BMDMs: bone marrow-derived macrophages; BV/TV: bone volume per total volume; CHX: cycloheximide; cKO: conditional knockout; co-IP: co-immunoprecipitation; CTSK: cathepsin K; DFO: deferoxamine; MDS: myelodysplastic syndrome; MUFA: monounsaturated fatty acid; NAE1: NEDD8 activating enzyme E1 subunit 1; NCOA4: nuclear receptor coactivator 4; NEDD8: NEDD8 ubiquitin like modifier; NFE2L2: NFE2 like bZIP transcription factor 2; NFATC1: nuclear factor of activated T cells 1; OC: osteoclast; OVX: ovariectomy; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; RUNX2: RUNX family transcription factor 2; SLC40A1: solute carrier family 40 member 1; SLC7A11: solute carrier family 7 member 11; Tb.N: trabecular number; Tb.Sp: trabecular separation; Tb.Th: trabecular thickness; TFRC: transferrin receptor; TNFSF11/RANKL: TNF superfamily member 11; UBE2M: ubiquitin conjugating enzyme E2 M.\n\nID: 42495756\nTitle: TPD54 contributes to docetaxel resistance through modulation of P\u2011glycoprotein localization and activity in oral squamous cell carcinoma cells.\nAbstract: Tumor protein D52 (TPD52) family proteins are involved in the proliferation, survival and malignant progression of oral squamous cell carcinoma (OSCC). However, their roles in chemoresistance remain incompletely understood. The present study investigated the contribution of TPD52 family proteins to anticancer drug resistance, with particular emphasis on tumor protein D54 (TPD54). OSCC cells were treated with cisplatin, 5\u2011fluorouracil, or docetaxel (DTX), and the expression of TPD52 family members was examined. Gain\u2011 and loss\u2011of\u2011function analyses were performed to evaluate cell viability, apoptotic responses, cytochrome p450 (P450) and P\u2011glycoprotein (P\u2011gp) activities, protein expression, intracellular localization and membrane/cytosol distribution. Anticancer drug treatment increased the expression of TPD52, TPD53 and TPD54. Among these family members, TPD54 showed the strongest association with DTX resistance by attenuating the reduction in cell viability without affecting cell\u2011cycle progression. TPD54 overexpression attenuated DTX\u2011associated apoptotic responses and was associated with changes in apoptosis\u2011, ferroptosis\u2011, and autophagy\u2011related marker proteins. TPD54 expression had little effect on the activities of P450 3A4 or P450 1B1 but significantly increased P\u2011gp activity. Membrane/cytosol fractionation demonstrated increased membrane localization of endogenous P\u2011gp following TPD54 overexpression, whereas co\u2011immunoprecipitation and immunocytofluorescence analyses revealed an association and partial co\u2011localization between TPD54 and P\u2011gp. These findings suggest that TPD54 contributes to DTX resistance in OSCC cells through modulation of P\u2011gp localization and activity. The present study identifies TPD54 as a potential contributor to P\u2011gp\u2011associated chemoresistance and provides a basis for further investigation of the molecular mechanisms underlying multidrug resistance in OSCC.\n\nID: 42495706\nTitle: NUPR1 in breast cancer: mechanisms and potential applications.\nAbstract: Breast cancer continues to present formidable clinical challenges, particularly in triple-negative and endocrine-resistant subtypes where adaptive stress mechanisms drive therapeutic failure. Nuclear protein 1 (NUPR1), an intrinsically disordered protein, has emerged as a non-mutational hub that has been implicated in integrating metabolic, transcriptional, and cell-survival signals associated with malignant progression. This Review examines how NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress. We discuss its causal roles in endocrine and chemoresistance through chromatin-associated cooperation with estrogen receptor \u03b1, activation of DNA-damage repair, and cell-cycle checkpoint control, as well as its contributions to metastatic dissemination via extracellular vesicle-mediated niche remodeling and immunosuppressive macrophage polarization. Furthermore, we evaluate emerging therapeutic avenues, from small-molecule inhibitors and single-domain antibody degraders that disrupt NUPR1 nuclear trafficking, to metabolic drug repurposing strategies such as statins that intercept the insulin-NUPR1 axis. Elucidating NUPR1 biology represents a paradigm shift toward targeting dynamic, stress-adaptive dependencies in breast cancer, offering new precision-oncology opportunities.\n\nID: 42495580\nTitle: Reactive oxygen species (ROS) in cancer: from redox signaling and metabolic plasticity to therapeutic vulnerabilities.\nAbstract: Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2-Keap1 axis to adapt to these conditions, leading to redox plasticity and \"Nrf2 addiction\" in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc-, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.\n\nID: 42495555\nTitle: Integrated network pharmacology, molecular docking, and experimental validation elucidate the anti-inflammatory and antioxidant mechanisms of apigenin in LPS-induced acute lung injury.\nAbstract: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are associated with high clinical mortality and lack effective therapeutic agents. The natural flavonoid apigenin possesses well-defined anti-inflammatory and antioxidant activities; however, its protective mechanism in ALI remains to be systematically elucidated. In this study, we established LPS-induced mouse models of ALI and BEAS-2B human bronchial epithelial cell injury models, combined with network pharmacology, molecular docking, and 100 ns molecular dynamics simulations, and employed the ferroptosis inhibitor Fer-1 and inducer Erastin for mechanistic validation, to comprehensively evaluate the protective effects of apigenin. Our results demonstrated that apigenin dose-dependently alleviated pulmonary histopathological damage, reduced inflammatory cell infiltration, myeloperoxidase activity, and the levels of pro-inflammatory cytokines IL-6, IL-1\u03b2, and TNF-\u03b1. Concurrently, apigenin inhibited the phosphorylation of NF-\u03baB and JAK2-STAT3 pathways, upregulated the expression of GPX4 and SLC7A11, decreased Fe2+ and malondialdehyde levels, and attenuated lipid peroxidation. These effects were similar to those of Fer-1 and were partially reversed by Erastin. Network pharmacology and molecular simulations revealed that apigenin stably binds to core targets including MMP9, EGFR, and ESR1, and KEGG enrichment analysis significantly pointed to the NF-\u03baB and JAK-STAT pathways. Collectively, apigenin effectively alleviates LPS-induced ALI through coordinated regulation of the NF-\u03baB/JAK2-STAT3 pathway and inhibition of inflammatory responses, ferroptosis, and oxidative stress, thus providing a novel theoretical basis and a candidate therapeutic strategy for the treatment of ALI with this flavonoid.\n\nID: 42494419\nTitle: Intra-arterial delivery of FePt nanoparticles induces ferroptosis and immune infiltration to enhance radiotherapy.\nAbstract: Recent advances in nanomedicine provide new opportunities to enhance radiotherapy and overcome tumor radioresistance. In this study, we investigated the therapeutic potential of iron-platinum nanoparticles (FePt NPs) delivered through intra-arterial (IA) administration to improve tumor targeting and therapeutic efficacy. FePt NPs significantly inhibited the proliferation of triple-negative breast cancer (TNBC) cells and enhanced radiosensitivity. Mechanistic studies demonstrated that FePt NPs induced ferroptosis characterized by lipid peroxidation (LPO), mitochondrial damage, and downregulation of GPX4, leading to the release of damage-associated molecular patterns (DAMPs), including ATP, high-mobility group box 1 (HMGB1), and calreticulin (CRT), thereby promoting ferroptosis-associated immunogenic cell death (ICD). In vitro cytokine array analysis further revealed modulation of immune-related cytokines associated with inflammatory responses and immune cell recruitment. In vivo studies showed that IA administration significantly increased FePt NPs accumulation within tumors compared with conventional intravenous delivery, resulting in enhanced tumor suppression. The combination of FePt NPs and radiotherapy further promoted T-cell and macrophage infiltration within the tumor microenvironment (TME), indicating enhanced immune activation. Importantly, in a comparative canine liver tumor model treated with FePt NPs via transarterial embolization, tumor regression or stabilization was observed together with increased immune infiltration. These findings demonstrate that IA-delivered FePt NPs act as ferroptosis-inducing radiosensitizers that reshape the tumor immune microenvironment and convert immunologically \"cold\" tumors into \"hot\" tumors. This approach highlights the translational potential of localized nanoparticle delivery for cancer radio-immunotherapy.\n\nID: 42494415\nTitle: MRI-enabled ferroptosis self-amplifying nanoplatform synergizes with photothermal therapy to enhance chemotherapeutic efficacy against pancreatic cancer.\nAbstract: Pancreatic cancer responds poorly to conventional chemotherapy, largely because of the pronounced resistance of tumor cells to chemotherapy-induced apoptosis. Ferroptosis, a non-apoptotic form of programmed cell death, has emerged as a promising strategy to overcome this resistance. However, its therapeutic efficacy is often limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) in the tumor microenvironment (TME). Herein, we developed a nanoplatform, HM-MnO2@DOX/CaO2@PDA/HA (HMDCPH), using hollow mesoporous manganese dioxide (HM-MnO2) as a carrier to co-deliver doxorubicin (DOX) and calcium peroxide (CaO2). The crosslinked PDA/HA shell enhanced both the tumor-targeting capability and biocompatibility of the nanoplatform. In the TME, HM-MnO2 depleted GSH and promoted reactive oxygen species (ROS) generation, whereas CaO2 decomposition generated H2O2 and released Ca2+, inducing mitochondrial calcium overload and further aggravating oxidative stress. These synergistic effects enhanced lipid peroxidation (LPO) and exacerbated ferroptosis-related oxidative damage. Moreover, the near-infrared (NIR)-triggered photothermal effect further strengthened the antitumor efficacy of HMDCPH. In addition, nanoplatform degradation released Mn2+, enabling T1-weighted magnetic resonance imaging (MRI). Collectively, this study presents a synergistic nanotherapeutic strategy that integrates chemotherapy, photothermal therapy, and ferroptosis-related mechanisms to overcome chemoresistance in pancreatic cancer.\n\nID: 42493297\nTitle: Autophagy in gastrointestinal cancers: Therapeutic and biological perspectives.\nAbstract: Gastrointestinal (GI) neoplasms are among the most common and lethal tumors around the world. In spite of the introduction of multiple conventional therapeutics for GI tumors, the treatment of these cancers is challenging. Moreover, they are able to mediate resistance to therapeutics. Therefore, the novel therapeutics should be developed for the treatment of GI tumors based on the underlying mechanisms. Autophagy is a programmed cell death mechanism dysregulated in human cancers and it is a potential therapeutic target. In the current review, a special focus is placed on the role of autophagy in GI neoplasms. The current studies have highlighted the fact that genomic and epigenetic factors can participate in the regulation of autophagy in GI tumors. Autophagy can exert protective function to enhance survival of cancer cells, while it decreases apoptosis, ferroptosis and other cell death mechanisms. On the other hand, the pro-death autophagy impairs the progression of GI tumors. In order to regulate autophagy in GI tumor therapy, the studies have focused on the development of drugs (synthetic drugs and natural compounds) along with nanoparticles for the autophagy modulation in GI cancer therapy. The autophagy-related factors can be considered as prognostic and diagnostic factors in GI tumors.\n\nID: 42492895\nTitle: Pyruvate Alleviates Traumatic Brain Injury by Suppressing Glutamate-Driven Ferroptosis via the xCT/GPX4 Axis.\nAbstract: Traumatic brain injury (TBI) triggers toxic glutamate release and ferroptosis, contributing to neuronal death. This study investigated whether sodium pyruvate confers neuroprotection by reducing central glutamate and inhibiting ferroptosis. Using a murine TBI model, we found that pyruvate treatment rapidly lowered serum glutamate levels by enhancing hepatic alanine aminotransferase (ALT) activity. Subsequently, cerebrospinal fluid (CSF) glutamate decreased, likely facilitated by a disrupted blood-brain barrier (BBB). Pyruvate restored the cystine/glutamate antiporter xCT (System Xc\u207b)/ glutathione peroxidase 4 (GPX4) antioxidant axis, increased glutathione, reduced lipid peroxidation, iron deposition, and improved mitochondrial function, thereby attenuating ferroptosis. These effects were abolished by the xCT inhibitor Erastin. Furthermore, pyruvate treatment reduced neuronal loss, decreased lesion volume, and improved long-term neurological and cognitive function in behavioral tests. In conclusion, intravenous pyruvate protects against TBI by peripherally scavenging glutamate and centrally inhibiting ferroptosis via the xCT/GPX4 pathway.\n\nID: 42492799\nTitle: Sodium-glucose cotransporter 1 exacerbates colon cancer malignancy by suppressing ferroptosis via the Nrf2/HO-1/SLC7A11/GPX4 axis under high glucose conditions.\nAbstract: Hyperglycemia is an independent risk factor for colon cancer progression, but its underlying mechanisms remain unclear. Ferroptosis is a form of programmed cell death, yet whether sodium-glucose cotransporter 1 (SGLT1) regulates ferroptosis to affect colon cancer under high glucose has not been reported. This study aims to clarify the mechanism by which SGLT1 regulates the malignant phenotype of colon cancer under high-glucose conditions and explore the therapeutic potential of targeting SGLT1 combined with ferroptosis inducers. HT29 and SW480 cells were treated with mmol/L high glucose. Cell proliferation and migration were detected by CCK-8, colony formation and wound-healing assays. Ribonucleic acid sequencing (RNA-seq) screened SGLT1-regulated downstream pathways. Ferroptosis was evaluated by malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), ferrous ions (Fe2+) levels and mitochondrial ultrastructure. Western blot detected nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway proteins. Interventions included ferrostatin-1 (Fer-1), tert-butylhydroquinone (TBHQ) and SLC7A11 overexpression. In vivo antitumor efficacy was assessed in diabetic nude mouse xenografts. High glucose significantly enhanced HT29 and SW480 cell viability, colony formation and migration, with upregulated SGLT1. SGLT1 knockdown reversed these phenotypes, while overexpression aggravated them. RNA-seq showed ferroptosis was the most enriched pathway after SGLT1 knockdown, with downregulated GPX4 and SLC7A11. Only Fer-1 reversed SGLT1 knockdown-induced cell viability decrease (78.5%, P<0.0001). SGLT1 knockdown increased MDA (3.53/3.40 vs. 2.33 nmol/mL, P<0.0001), ROS (6.91/7.12 vs. 3.57 a.u., P<0.01) and Fe2+ (44.50/44.74 vs. 8.54 a.u., P<0.0001), decreased GSH (35.93/37.04 vs. 46.96 \u03bcg/mL, P<0.0001), and induced mitochondrial atrophy; overexpression had opposite effects. SLC7A11 overexpression restored GPX4 (0.97 vs. 0.40, P=0.0187) and reversed ferroptosis and growth inhibition. SGLT1 knockdown suppressed Nrf2/HO-1, which was rescued by TBHQ, increasing HO-1 (1.03 vs. 0.62, P=0.0218), SLC7A11 (0.99 vs. 0.56, P=0.0303) and GPX4 (1.37 vs. 0.30, P=0.0065), while concurrently reversing ferroptosis. In vivo, SGLT1 knockdown reduced tumor weight from 264.6 to 36.76 mg (P<0.0001); mizagliflozin plus erastin achieved 90.69% tumor inhibition (Bliss score 0.087). High glucose promotes colon cancer cell proliferation and migration by upregulating SGLT1. SGLT1 is a key driver of high glucose-induced colon cancer malignant phenotypes. SGLT1 knockdown inhibits colon cancer mainly by activating ferroptosis, characterized by increased lipid peroxidation, GSH depletion, iron accumulation and mitochondrial atrophy. SGLT1 regulates ferroptosis via the SLC7A11/GPX4 axis. It inhibits ferroptosis by activating Nrf2/HO-1 to upregulate SLC7A11 and GPX4. Targeting SGLT1 enhances colon cancer cell sensitivity to ferroptosis inducers. Combined targeting of SGLT1 and ferroptosis is a novel therapeutic strategy for diabetic colon cancer patients.\n\nID: 42492764\nTitle: Astragaloside IV ameliorates diabetic kidney disease by modulating the PHD2/HIF-1\u03b1 axis and inhibiting podocyte ferroptosis.\nAbstract: Diabetic kidney disease (DKD) lacks therapies that directly target podocyte injury, and the upstream regulation of HIF-1\u03b1-driven ferroptosis in podocytes remains unclear. This study investigated whether astragaloside IV (AS-IV) protects against DKD by regulating the PHD2/HIF-1\u03b1 axis. A DKD mouse model was induced by a high-fat/high-sugar diet plus streptozotocin, followed by AS-IV intervention (100\u202fmg/kg/day for 12\u202fweeks). In vitro, podocytes were exposed to high glucose (30\u202fmM) with AS-IV (40\u202f\u03bcmol/L), along with the HIF-1\u03b1 inhibitor LW6 or activator DMOG. Network pharmacology and molecular docking identified HIF-1\u03b1 signaling as a core pathway, with stable binding of AS-IV to PHD2 and HIF-1\u03b1. AS-IV improved renal function and pathology in DKD mice without affecting blood glucose. In vivo and in vitro, AS-IV activated PHD2, promoted HIF-1\u03b1 ubiquitination and degradation, and subsequently inhibited podocyte ferroptosis, as shown by reduced iron accumulation and lipid peroxidation, and upregulated GPX4 and SLC7A11. Additionally, AS-IV suppressed pyroptosis and inflammation (reduced NLRP3, GSDMD-NT, IL-1\u03b2, IL-18) and modulated apoptosis (increased Bcl2). In conclusion, the renoprotective effect of AS-IV is mediated through the PHD2/HIF-1\u03b1 axis, reducing HIF-1\u03b1 accumulation and thereby inhibiting podocyte ferroptosis, pyroptosis, inflammation, and fibrosis in DKD. These findings provide a novel mechanistic foundation for AS-IV as a prospective therapeutic agent for DKD.\n\nID: 42492703\nTitle: Jiajian Shuyu Pills Ameliorates Cerebral Ischemia-Reperfusion Injury by Regulation Hippo signaling and the Lipid Metabolism-Ferroptosis Axis.\nAbstract: Ischemic stroke is a life-threatening cerebrovascular disease characterized by focal injury to the central nervous system. Jiajian Shuyu Pills (JJSYP), a modified traditional Chinese medicine formulation derived from Shuyu Pills, consist of multiple herbs, including Rhizoma Dioscoreae, Polygonum multiflorum Thunb, Rehmannia glutinosa Libosch, Codonopsis pilosula, Nannf, Atractylodes macrocephala Koidz, Poria cocos (Schw.) Wolf, Paeonia lactiflora Pall, Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong Hort, Eucommia ulmoides Oliv, Polygala tenuifolia Willd, Acorus tatarinowii Schott, Lycium barbarum L, and Schisandra chinensis (Turcz.) Baill. JJSYP show therapeutic potential for ischemic stroke; however, their bioactive components and molecular mechanisms remain insufficiently defined. This study aimed to evaluate the therapeutic efficacy of JJSYP against cerebral ischemia-reperfusion injury (CIRI) and to elucidate its underlying molecular mechanisms through comprehensive multi-omics integration, thereby providing a scientific basis for the clinical application of JJSYP and the development of novel therapeutic strategies for CIRI. A systematic, multi-step experimental strategy was employed. The protective effects of JJSYP against CIRI-induced neurological deficits were evaluated in a transient middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model, in which mice underwent 1 h of middle cerebral artery occlusion followed by 24 h of reperfusion. And proteomic analysis was performed to identify differentially expressed proteins and predict the signaling pathways involved in the anti-CIRI effects of JJSYP. Then, the bioactive components of JJSYP were identified through chemical profiling combined with network pharmacology. Untargeted metabolomics was used to characterize changes in metabolic profiles, and a \"component-target-metabolite-pathway\" network was constructed to clarify their potential associations. Finally, molecular biological experiments and lipidomic analysis were conducted to validate the anti-CIRI mechanisms of JJSYP. In vivo experiments showed that JJSYP significantly alleviated cerebral tissue injury and improved neurological function in CIRI mice. Proteomic analysis indicated that JJSYP may mitigate CIRI primarily by regulating the Hippo signaling pathway, which is closely associated with cell survival, proliferation, and apoptosis. Integrated network pharmacology and metabolomics analyses identified six core JJSYP components that potentially modulate seven key targets and regulate six critical CIRI-related metabolic pathways. Validation experiments further confirmed that JJSYP modulated Hippo signaling-related proteins, including p-YAP/YAP, SOX2, and YWHAZ, and improved lipid peroxidation- and ferroptosis-related markers, such as 4-HNE, ACSL4, and PLA2G2A, suggesting that JJSYP may exert anti-CIRI effects by regulating Hippo signaling and the lipid metabolism-ferroptosis axis. This is the first study to systematically investigate the potential anti-CIRI mechanisms of JJSYP through multi-omics analysis. The findings preliminarily suggest that JJSYP alleviates CIRI by modulating the Hippo signaling pathway and the lipid metabolism-ferroptosis axis. This study provides preclinical scientific evidence for the therapeutic effects of JJSYP and offers a feasible strategy for elucidating the mechanisms of traditional Chinese medicine formulas, thereby facilitating their modernization and internationalization.\n\nID: 42492190\nTitle: From ROS to Cuproptosis: The molecular evolution of copper nanotherapeutics.\nAbstract: The renewed interest in copper-based materials for biomedical applications has been catalyzed by advances in nanotechnology, shifting the paradigm from empirical antimicrobial therapies toward multifunctional nanoplatforms capable of targeted intervention and theranostic integration. This work provides a systematic assessment of the developmental trajectory of copper-containing nanostructures-ranging from single-component Cu, CuO, and Cu2O particles to shape-anisotropic architectures, polymer composites, and ultimately bimetallic combinations, with particular emphasis on Cu/Se systems. A central thesis advanced here is that the bioactivity of these agents cannot be attributed to a single intrinsic parameter; rather, it emerges from a convoluted interplay of size, morphology, surface potential, oxidation state, shell composition, and, notably, the aggregation behavior in physiological fluids-the latter being frequently obscured by protein corona artifacts. Moving beyond conventional reactive oxygen species (ROS)-driven oxidative injury and mitochondrial apoptotic cascades, recent molecular toxicology has identified two non-apoptotic, copper-relevant cell death modalities: cuproptosis, characterized by aggregation of lipoylated mitochondrial proteins via the ferredoxin 1 (FDX1), and ferroptosis, involving glutathione peroxidase 4 (GPX4) inhibition and intracellular glutathione exhaustion. These pathways, together with the phenomenon of cuproplasia in malignant cells, offer unprecedented opportunities for selective therapeutic intervention. Among all structural classes, bimetallic Cu/Se nanoparticles represent a \"reconciliation of redox opposites,\" wherein the pro-oxidant Fenton-like activity of copper is counterbalanced by selenium's antioxidant, photothermal (conversion efficiency exceeding 80%), and regulatory functionalities, leading to substantially improved therapeutic indices and diminished off-target effects. Anisotropic configurations-including nanoflowers and nanorods-further enable multimodal diagnostic imaging and combined therapy, yet their clinical translation is constrained by difficulties in morphological reproducibility and in vivo clearance mechanisms. While clinical adoption remains largely confined to topical indications (e.g., CuO-embedded wound dressings that have demonstrated significant reductions in surgical site infections in randomized trials), the emerging mechanistic framework centered on cuproptosis and hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) modulation positions copper-based nanoplatforms as strong contenders for future theranostic applications. The review concludes that the field must prioritize a \"clearance-by-design\" philosophy, implement standardized green synthesis protocols, and conduct comprehensive long-term biodistribution and toxicity studies in vivo to close the existing gap between robust preclinical evidence and tangible clinical impact.\n\nID: 42492176\nTitle: Quercetin alleviates high fluoride-induced hepatocyte ferroptosis via regulating the ROS/PERK signaling pathway.\nAbstract: Ferroptosis is closely associated with fluoride-induced liver injury. As a natural flavonoid with potent anti-ferroptotic activity, quercetin (Que) could mitigate fluoride-triggered hepatotoxicity. Therefore, the aim of this study was to investigate the protective effects of Que against sodium fluoride (NaF)-induced ferroptosis and to elucidate its molecular mechanisms. In vivo data demonstrated that Que restored liver function, ameliorated hepatic pathological lesions, and alleviated mitochondrial damage in NaF-exposed mice. Additionally, Que suppressed NaF-induced apoptosis and inflammation. Both in mouse liver tissues and AML-12 cells, Que exerted anti-ferroptotic actions via restraining reactive oxygen species (ROS) and lipid peroxidation, alleviating iron overload, increasing reduced to oxidized glutathione (GSH/GSSG) ratio and GSH content, altering the expression of ferroptosis-related proteins including glutathione peroxidase 4, Acyl-CoA synthetase long-chain family member 4, transferrin receptor, and ferritin heavy chain 1. Mechanistically, molecular docking combined with molecular dynamics simulations indicated the high reliability and stability of Que binding to Protein kinase R-like ER kinase (PERK). Que inhibited the activation of PERK signaling pathway. Pharmacological intervention assays verified that PERK inhibitor GSK2606414 mimicked Que's anti-ferroptotic effects, whereas PERK agonist CCT abolished Que-mediated protection against NaF-induced ferroptosis. Importantly, ROS elimination by N-acetylcysteine suppressed PERK activation and subsequent ferroptosis triggered by NaF. Overall, Que mitigates NaF-induced hepatic ferroptosis via inhibiting the ROS/PERK signaling pathway, highlighting its potential therapeutic application against high fluoride-induced hepatotoxicity.\n\nID: 42492013\nTitle: Targeting the NR3C1-ACSL4 Axis Triggers Ferroptosis to Overcome Radioresistance in Prostate Cancer.\nAbstract: Radioresistance in prostate cancer demands innovative sensitization strategies. We identified the glucocorticoid receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) as a key negative regulator of radiosensitivity linked to poor prognosis. NR3C1 transcriptionally upregulates the lipid-metabolizing enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby enhancing cell proliferation, migration, and radioresistance. High ACSL4 expression sensitizes cells to ferroptosis inducers that amplify lipid peroxidation and restore radiosensitivity. Using the clinically applicable ferroptosis inducer, dihydroartemisinin (DHA), we found that DHA synergizes with ACSL4 to trigger ferroptosis, sensitizing radioresistant cells and xenografts to radiation. This effect was characterized by elevated lipid peroxidation and was reversed by the ferroptosis inhibitor deferoxamine. Collectively, our study revealed that the NR3C1-ACSL4 axis regulates lipid peroxidation and promotes radioresistance. Targeting this axis with DHA and using ACSL4 as a biomarker represents a promising preclinical strategy to overcome radioresistance in prostate cancer, pending further clinical validation.\n\nID: 42491529\nTitle: Metal-dependent regulated cell death: Molecular architecture and translational frontiers.\nAbstract: Intracellular metal dyshomeostasis has emerged as a key regulator of specialized regulated cell death (RCD) programs, challenging classical views that regard necrosis as entirely accidental. This review systematically delineates the molecular architecture and translational trajectories underlying metal-dependent RCD, including iron-driven ferroptosis, copper-mediated cuproptosis, and additional emerging modalities such as calcicoptosis, necrosis by sodium overload (NECSO), and the newly designated zincoptosis, mnoptosis, and coptosis. We examined distinct execution mechanisms, ranging from membrane lipid peroxidation and lipoylation-targeted proteotoxic stress to organelle-specific bioenergetic failure, which arise following disruption of compartmentalized metal-buffering networks. To bridge the persistent knowledge gap between foundational metallobiology and clinical application, we evaluated a bidirectional therapeutic framework: exploiting synthetic lethality and metabolic gating via clinical inducers (e.g., sorafenib, elesclomol) to selectively eliminate therapy-resistant malignancies while deploying targeted pathway inhibitors and systemic agonists (e.g., dipyridamole, omaveloxolone) to limit pathological tissue degeneration in ischemic and neurodegenerative disorders. Recognizing that off-target multiorgan toxicity and complex in vivo crosstalk among interconnected death pathways (e.g., disulfidptosis and PANoptosis) represent major translational challenges, we assessed advanced materials-science strategies designed to overcome these barriers. Specifically, we highlighted the integration of single-atom catalysts, stimuli-responsive nanomedicines, and biomimetic carriers engineered to spatiotemporally confine catalytic oxidative flux. Finally, we examined the systemic immunological consequences of targeted metal dysregulation, detailing how metal-induced immunogenic cell death and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway hyperactivation reshape immunosuppressive microenvironments and modulate sterile inflammation, thereby enhancing responsiveness to immune checkpoint blockade, providing a definitive molecular blueprint for next-generation precision therapeutics.\n\nID: 42490842\nTitle: Modulation of oxidative stress and plant responses to salinity by nanosilicon: current insights and future perspectives.\nAbstract: Soil salinity is a formidable challenge to global food security, triggering severe oxidative stress and reactive oxygen species (ROS) overproduction that devastate crop productivity. Nanosilicon (1-100 nm) has recently emerged as a transformative, highly reactive elicitor capable of counteracting these detrimental effects more efficiently than conventional bulk silicon. This comprehensive review critically evaluates the underlying mechanisms of nanosilicon-mediated salt tolerance and its practical implications for sustainable agriculture. By offering superior cellular penetration and bioavailability, nanosilicon mitigates ROS, such as superoxide radicals (O2 -) and hydrogen peroxide (H2O2), subsequently reducing lipid peroxidation by up to 50% across various crops. Beyond direct scavenging, it fortifies both enzymatic and non-enzymatic antioxidant defense systems and modulates stress-responsive gene networks via abscisic acid (ABA) and mitogen-activated protein kinase (MAPK) signaling cascades. By synergizing osmotic adjustment, ion homeostasis, and photosynthetic protection, these nanoscale interventions can drive yield improvements of up to 30% under saline conditions. Crucially, we address the current limitations, emphasizing that nanosilicon's efficacy is highly dependent on plant species, particle size, and environmental variables. While challenges such as dose-dependent phytotoxicity, environmental risks, and production costs require further investigation, optimizing nanosilicon formulations holds profound potential for developing climate-resilient agriculture.\n\nID: 42490743\nTitle: A Self-Reinforcing LipoTIDE Nanoplatform That Overcomes Lipid-Buffering Ferroptosis Resistance for Enhanced Cancer Therapy.\nAbstract: Lipid metabolic rewiring is a hallmark of malignancy, allowing tumor cells to sequester fatty acids within lipid droplets (LDs) as a protective reservoir that quenches reactive oxygen species (ROS)-driven lipid peroxidation and thereby evades ferroptosis. Although lipophagy selectively degrades LDs to release free fatty acids (FFAs) and remodel lipid homeostasis, leveraging this process to overcome lipid-buffering ferroptosis resistance remains largely unexplored. Here, we report LipoTIDE (Lipophagy-Tuning Induced Death Enhancer), a self-reinforcing nanoplatform that primes lipophagy-primed ferroptosis by coupling precise lipophagy activation with catalytic ROS generation to dismantle LDs-mediated metabolic defenses in tumors. LipoTIDE co-delivers ultrasmall Pt3Co nanoalloys and tamoxifen within a pH-responsive amphiphilic polymer, enabling tumor-targeted disassembly and localized therapeutic amplification. Triggered by the tumor acidity, LipoTIDE releases Pt3Co nanoalloys for multiple catalytic activities and tamoxifen for initiating lipophagy and decreasing pH value, establishing a self-reinforcing loop that sustains lipophagy and ferroptosis. Additionally, FFAs from lipophagy, together with the Pt3Co nanoalloys, resensitize resistant cancer cells to Pt3Co-catalyzed ROS, thereby amplifying ferroptosis. Consequently, LipoTIDE precisely disrupts lipid homeostasis, triggers robust ferroptotic tumor suppression, and exhibits minimal systemic toxicity. These findings establish lipophagy-primed ferroptosis as a generalizable and actionable strategy for dismantling lipid-buffering defenses of tumors.\n\nID: 42489635\nTitle: Mechanism of lovastatin in promoting ferroptosis of prostate cancer cells by regulating the mevalonate pathway.\nAbstract: Prostate cancer (PCa) is a common malignancy in men with limited therapeutic options at advanced stages. Statins, widely prescribed lipid-lowering agents, have demonstrated antitumor activity in PCa, but underlying mechanisms are not fully understood. Studies suggested that tumor progression is facilitated upon activation of mevalonate (MVA) pathway, while it is reduced via MVA pathway inhibition-induced ferroptosis. Therefore, this study aimed to determine whether lovastatin suppresses prostate cancer progression by inducing ferroptosis through inhibition of the MVA pathway. Five clinically used statins were screened in prostate cancer cell lines to identify the most effective compound. Cell proliferation, migration, and invasion were assessed. Ferroptosis was evaluated by measuring intracellular Fe2+ and reactive oxygen species (ROS) levels, mitochondrial membrane potential, ferroptosis-related protein expression, and ultrastructural mitochondrial alterations. Rescue experiments were performed using the ferroptosis inhibitor deferoxamine and MVA supplementation. Lovastatin exhibited the strongest inhibitory effect, significantly reducing proliferation, migration, and invasion. Lovastatin significantly suppressing PCa cell aggressiveness and inducing ferroptosis, as evidenced by typical biochemical and morphological markers, all of which were reversed by deferoxamine. MVA supplementation restored cell viability, normalized oxidative stress and iron levels, and reversed alterations in MVA pathway enzymes and ferroptosis-associated proteins. Lovastatin suppresses prostate cancer cell growth and invasiveness by inhibiting the MVA pathway and inducing ferroptosis, highlighting the MVA-ferroptosis axis as a potential therapeutic target for PCa.\n\nID: 42489363\nTitle: Effects of Isorhapontigenin on Cell Viability, Colony-Forming Efficiency, and Ferroptosis via Methyltransferase-Like 14-Mediated m6A Modification of Solute Carrier Family 7 Member 11 in Human Epidermal Growth Factor Receptor 2-Enriched and Basal-Like Breast Cancer.\nAbstract: As a key regulator of N6-methyladenosine (m6A) modification, methyltransferase-like 14 (METTL14) has been implicated in the progression of various cancers; however, its functional role in breast cancer remains controversial. Isorhapontigenin (ISO), a natural polyphenolic compound, has been identified as a METTL14 agonist with antitumor potential in multiple malignancies. Nevertheless, the biological function of ISO in breast cancer, particularly its mechanism of regulating METTL14 and downstream signaling pathways, has not been fully elucidated. This study aimed to explore the effects of ISO on breast cancer cell viability, colony-forming efficiency, and ferroptosis and investigate whether ISO exerts these effects by regulating METTL14 expression. Bioinformatics analyses were performed to identify differentially expressed m6A-related genes in breast cancer tissues. CCK-8 and colony formation assays were used to evaluate the effects of ISO on breast cancer cell viability and colony-forming efficiency. Ferroptosis was assessed by quantifying ferroptosis-related indicators, including reactive oxygen species, glutathione, malondialdehyde, and intracellular Fe2+ levels. METTL14-overexpressing cell lines, as well as METTL14- and SLC7A11-silenced cell lines, were constructed to explore gene functions. Bioinformatics analysis revealed that METTL14 is downregulated in basal-like and HER2-enriched breast cancer subtypes, and METTL14 overexpression suppressed cell viability and colony-forming efficiency and promoted ferroptosis in these METTL14-low subtypes. ISO also suppressed cell viability and colony-forming efficiency and induced ferroptosis in these cell subtypes. Mechanistically, ISO exerted its effects by upregulating METTL14 expression, which in turn induced m6A modification of SLC7A11 mRNA. In conclusion, ISO reduced cell viability and colony-forming efficiency, and promoted ferroptosis in HER2-enriched and basal-like breast cancer cells through promoting METTL14-dependent m6A modification of SLC7A11 mRNA. These findings suggest that ISO may serve as a candidate therapeutic agent for the treatment of HER2-enriched and basal-like breast cancer.\n\nID: 42488685\nTitle: Potential crosstalk between ferroptosis and immunosenescence in osteoarthritis: evidence integration and translational insights from the osteoimmune microenvironment.\nAbstract: Osteoarthritis (OA) has traditionally been regarded as a degenerative disease primarily characterized by cartilage wear and tear. However, accumulating evidence suggests that it is fundamentally a whole-joint disorder involving the coordinated participation of cartilage, synovium, subchondral bone, and immune components. In recent years, ferroptosis and immunosenescence have each been recognized as contributors to OA initiation and progression, yet their potential interplay within the osteoimmune microenvironment remains insufficiently integrated. This review summarizes how iron homeostasis imbalance, lipid peroxidation, and impaired antioxidant defense promote ferroptosis in joint-resident cells, and how immunosenescence influences joint homeostasis through chronic low-grade inflammation and functional remodeling. It further analyzes the possible crosstalk between these two processes in cartilage, synovium, subchondral bone, and related immune cells. In addition, this review outlines current advances in therapeutic strategies, including anti-ferroptotic interventions, anti-senescence modulation, and optimization of local delivery approaches. At present, direct evidence supporting a stable causal loop between ferroptosis and immunosenescence in OA remains limited, and many of the proposed mechanisms are still largely derived from in vitro studies, animal models, and extrapolation from other disease contexts. Therefore, this review aims to provide a testable working framework for understanding the link between ferroptosis and immunosenescence in OA from the perspective of the osteoimmune microenvironment and evidence stratification, and to offer reference for the development of future mechanism-oriented therapeutic strategies.\n\nID: 42487470\nTitle: MiR-199a-5p aggravates hypoxia/reoxygenation-induced cardiomyocyte ferroptosis by blocking HSPB1-Keap1/Nrf2/ARE signaling.\nAbstract: Ferroptosis plays a crucial role in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and acute myocardial infarction (AMI), yet the involvement of microRNA-199a-5p (miR-199a-5p) in this process remains insufficiently understood. In this study, serum miR-199a-5p levels were markedly elevated in AMI patients and positively correlated with myocardial injury markers cardiac troponin I and creatine kinase-MB, while H/R stimulation similarly upregulated miR-199a-5p expression in AC16 cardiomyocytes. Functional experiments demonstrated that miR-199a-5p overexpression exacerbated oxidative stress and ferroptosis, as evidenced by increased lactate dehydrogenase release, malondialdehyde production, Fe\u00b2+ accumulation, lipid peroxidation, and glutathione depletion, whereas miR-199a-5p inhibition conferred significant protection against H/R-induced injury. Mechanistically, heat shock protein \u03b2\u20111 (HSPB1) was identified as a direct downstream target of miR-199a-5p, with HSPB1 overexpression alleviating and its silencing aggravating ferroptotic responses under H/R conditions. Rescue assays further confirmed that HSPB1 mediates the pro-ferroptotic effects of miR-199a-5p. At the molecular level, the miR-199a-5p/HSPB1 axis regulated key ferroptosis-related proteins, including ACSL4, SLC7A11, and GPX4, and disrupted Keap1/Nrf2/ARE antioxidant signaling during H/R injury. Collectively, these findings indicate that miR-199a-5p aggravates H/R-induced cardiomyocyte ferroptosis by suppressing HSPB1 and impairing Nrf2-dependent antioxidant defense, suggesting that circulating miR-199a-5p may serve as a biomarker of myocardial injury and a potential therapeutic target in ischemic heart disease.\n\nID: 42487045\nTitle: BMSC-derived exosomal METTL3 synergizes with Sevoflurane to inhibit ferroptosis in pulmonary ischemia/reperfusion injury by enhancing USP7 N6-methyladenosine modification.\nAbstract: Inhibition of ferroptosis was shown to alleviate pulmonary ischemia/reperfusion (I/R) injury. This study aimed to investigate the synergistic effects of bone marrow mesenchymal stem cells (BMSC)-derived exosomal METTL3 and Sevoflurane (Sev) in alleviating pulmonary I/R injury through ferroptosis regulation. In our study, pulmonary I/R injury models were established in mice and lung microvascular endothelial cells (LMECs). Commercial kits were used to measure myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and iron content. Lipid peroxidation was determined using the BODIPY 581/591 C11 probe by flow cytometry. Total m6A modification was measured by the commercial kit and m6A dot blot, while m6A modification of USP7 mRNA was analyzed by MeRIP and polysome profiling. The interaction between proteins or RNAs was analyzed by Co-IP, FISH combined with immunofluorescence, RNA pull-down, RIP, or dual-luciferase reporter assay. We proved Sev preconditioning mitigated ferroptosis in pulmonary I/R injury by activating the Nrf2 pathway. Co-treatment with BMSC-derived exosomes potentiated the protective effects of Sev by promoting USP7-mediated Nrf2 deubiquitination modification. Mechanistically, BMSC-derived exosomal METTL3 promoted USP7 mRNA translation through YTHDC2-dependent m6A modification. Also, METTL3 knockdown in exosomes suppressed the Nrf2 pathway and exacerbated ferroptosis, while METTL3 overexpression showed opposite effects. YTHDC2 knockdown abolished these protective effects caused by METTL3-overexpressed exosomes. In conclusion, BMSC-derived exosomal METTL3 reinforced the protective effects of Sev by promoting USP7 mRNA translation via YTHDC2-dependent m6A modification. Upregulated USP7 subsequently facilitated Nrf2 deubiquitination, thereby inhibiting ferroptosis and protecting against pulmonary I/R injury.\n\nID: 42486993\nTitle: PLA2G2F suppresses ferroptosis through phospholipid remodeling.\nAbstract: Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation, and it has emerged as a potential therapeutic vulnerability of cancer. Here we identify the secretory phospholipase PLA2G2F (phospholipase A2 group IIF) as a ferroptosis suppressor in bladder cancer and elucidate its regulation and mechanism of action. PLA2G2F functions through an intracellular mechanism by localizing to the endoplasmic reticulum to inhibit ferroptosis. Our genetic and pharmacological analyses reveal that peroxisome proliferator-activated receptor \u03b3 (PPARG), a nuclear hormone receptor and transcription factor previously implicated in ferroptosis regulation, upregulates PLA2G2F and that PPARG-mediated ferroptosis resistance is largely dependent on PLA2G2F in bladder cancer. Further, lipidomic profiling suggests that PLA2G2F preferentially acts on ether-linked phospholipids containing polyunsaturated fatty acids, thereby reducing the pool of peroxidation-prone polyunsaturated fatty acid-containing phospholipids. Together, our findings establish PLA2G2F as an endoplasmic reticulum-resident ferroptosis suppressor regulated by PPARG and show that inhibiting PPARG signaling or PLA2G2F activity can sensitize bladder cancer cells to ferroptosis induction.\n\nID: 42486819\nTitle: [Gastrodin alleviates hypobaric hypoxia-induced brain injury in rats by reducing neuronal ferroptosis via the P53/SLC7A11/GPX4 signaling axis].\nAbstract: To investigate the neuroprotective effect of gastrodin (GAS) against hypobaric hypoxia (HH)-induced brain injury in rats and the underlying mechanism. Twenty-four adult SD rats were randomized equally into normoxic control group, HH model group, low-dose (100 mg/kg) GAS group (HH+GAS-L group), and high-dose (200 mg/kg) GAS group (HH+GAS-H group). In the latter 3 groups, the rats were exposed to HH in a hypobaric oxygen chamber for 24 h to simulate the condition at an altitude of 6000 m, and GAS was administered intraperitoneally once daily for 7 days. Cerebral cortex tissues were collected for analysis of P53, SLC7A11, and GPX4 protein expressions using Western blotting and for determination of the levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ion (Fe\u00b2\u207a). In cultured HT22 neurons exposed to oxygen-glucose deprivation (OGD), the effects of GAS (500 \u03bcmol/L), nutlin-3 (a P53 agonist; 10 \u03bcmol/L) or their combination were examined on ferroptosis-related protein expressions, intracellular ROS, lipid peroxidation, MDA, GSH, cell viability, mitochondrial membrane potential, and Fe\u00b2\u207a levels. In the rat models of HH, GAS treatment significantly inhibited P53 expression, upregulated SLC7A11 and GPX4 proteins, markedly reduced Fe\u00b2\u207a, ROS, and MDA levels, and increased GSH content in the cerebral cortex. In cultured HT22 neurons, GAS treatment effectively alleviated OGD-induced cell ferroptosis as shown by decreased P53 expression, increased SLC7A11 and GPX4 expressions, and lowered levels of intracellular ROS generation, lipid peroxidation, and Fe\u00b2\u207a accumulation, along with obvious restoration of GSH levels, cell viability, and mitochondrial membrane potential. The protective effects of GAS was markedly attenuated by activation of the P53 pathway using nutlin-3. GAS produces neuroprotective effects against HH-induced brain injury in rats by inhibiting neuronal ferroptosis via regulating the P53/SLC7A11/GPX4 signaling pathway. \u76ee\u7684: \u7814\u7a76\u5929\u9ebb\u7d20\uff08GAS\uff09\u5bf9\u9ad8\u539f\u4f4e\u538b\u7f3a\u6c27\uff08HH\uff09\u6027\u8111\u635f\u4f24\u7684\u795e\u7ecf\u4fdd\u62a4\u4f5c\u7528\uff0c\u5e76\u63a2\u8ba8\u5176\u673a\u5236\u662f\u5426\u4e0e\u8c03\u8282P53/SLC7A11/GPX4\u4fe1\u53f7\u901a\u8def\u3001\u6291\u5236\u795e\u7ecf\u5143\u94c1\u6b7b\u4ea1\u76f8\u5173\u3002\u65b9\u6cd5: \u4f53\u5185\u5b9e\u9a8c\u9009\u53d624\u53ea\u6210\u5e74SD\u5927\u9f20\uff0c\u968f\u673a\u5206\u4e3a4\u7ec4\uff08n=6\uff09:\u5e38\u538b\u5e38\u6c27\u5bf9\u7167\u7ec4\uff08Nor\uff09\u3001\u4f4e\u538b\u7f3a\u6c27\u6a21\u578b\u7ec4\uff08HH\uff09\u3001\u5929\u9ebb\u7d20\u4f4e\u5242\u91cf\u7ec4\uff08HH+GAS-L\uff0c100 mg/kg\uff09\u3001\u5929\u9ebb\u7d20\u9ad8\u5242\u91cf\u7ec4\uff08HH+GAS-H\uff0c200 mg/kg\uff09\u3002\u9664\u5bf9\u7167\u7ec4\u5916\uff0c\u5176\u4f59\u5404\u7ec4\u5927\u9f20\u7f6e\u4e8e\u6a21\u62df\u6d77\u62d46000 m\u7684\u4f4e\u538b\u6c27\u8231\u4e2d\u6301\u7eed\u66b4\u973224 h\u4ee5\u5efa\u7acbHH\u6a21\u578b\u3002\u5929\u9ebb\u7d20\u4e8e\u9020\u6a21\u540e\u8179\u8154\u7ed9\u836f\uff0c1\u6b21/d\u3002\u53d6\u7b2c7\u5929\u7684\u8111\u76ae\u5c42\u8fdb\u884cWestern blotting\u68c0\u6d4bP53\u3001SLC7A11\u53caGPX4\u86cb\u767d\u8868\u8fbe\uff0c\u540c\u65f6\u6d4b\u5b9a\u7ec4\u7ec7\u5185\u6d3b\u6027\u6c27\u6807\u5fd7\u7269\uff08DHE\uff09\u3001\u4e19\u4e8c\u919b\uff08MDA\uff09\u3001\u8c37\u80f1\u7518\u80bd\uff08GSH\uff09\u53ca\u4e9a\u94c1\u79bb\u5b50\uff08Fe\u00b2\u207a\uff09\u7684\u542b\u91cf\u3002\u4f53\u5916\u57f9\u517bHT22\u795e\u7ecf\u5143\uff0c\u5206\u4e3a:\u5bf9\u7167\u7ec4\uff08Control\uff09\u3001\u6a21\u578b\u7ec4\uff08OGD\uff09\u3001\u5929\u9ebb\u7d20\u5e72\u9884\u7ec4\uff08OGD+GAS\uff0c500 \u03bcmol/L\uff09\u3001P53\u6fc0\u52a8\u5242\u7ec4\uff08OGD+Nutlin-3\uff0c10 \u03bcmol/L\uff09\u53ca\u8054\u5408\u5904\u7406\u7ec4\uff08OGD+GAS+Nutlin-3\uff09\u3002\u68c0\u6d4b\u6307\u6807\u5305\u62ec\u94c1\u6b7b\u4ea1\u76f8\u5173\u86cb\u767d\u8868\u8fbe\u3001\u7ec6\u80de\u5185\u6d3b\u6027\u6c27\uff08DCFH-DA\uff09\u3001\u8102\u8d28\u8fc7\u6c27\u5316\uff08BODIPY-C11\uff09\u3001MDA\u3001GSH\u3001\u7ec6\u80de\u5b58\u6d3b\u7387\uff08CCK-8\uff09\u3001\u7ebf\u7c92\u4f53\u819c\u7535\u4f4d\uff08JC-1\uff09\u53ca\u4e9a\u94c1\u79bb\u5b50\uff08FerroOrange\uff09\u3002\u7ed3\u679c: \u52a8\u7269\u5b9e\u9a8c\u663e\u793a\uff0c\u4e0eHH\u7ec4\u76f8\u6bd4\uff0c\u5929\u9ebb\u7d20\u663e\u8457\u6291\u5236P53\u8868\u8fbe\uff0c\u4e0a\u8c03SLC7A11\u4e0eGPX4\u86cb\u767d\u6c34\u5e73\uff08P<0.05\uff09\uff0c\u5e76\u663e\u8457\u964d\u4f4e\u8111\u76ae\u5c42\u7ec4\u7ec7Fe\u00b2\u207a\u3001ROS\u548cMDA\u542b\u91cf\uff0c\u63d0\u9ad8GSH\u6c34\u5e73\uff08P<0.05\uff09\u3002\u7ec6\u80de\u5b9e\u9a8c\u7ed3\u679c\u4e00\u81f4\uff0c\u5929\u9ebb\u7d20\u6709\u6548\u51cf\u8f7b\u4f4e\u538b\u7f3a\u6c27\u8bf1\u5bfc\u7684\u94c1\u6b7b\u4ea1\uff0c\u8868\u73b0\u4e3aP53\u8868\u8fbe\u4e0b\u964d\uff0cSLC7A11\u4e0eGPX4\u8868\u8fbe\u5347\u9ad8\uff08P<0.05\uff09\uff0c\u7ec6\u80de\u5185ROS\u751f\u6210\u3001\u8102\u8d28\u8fc7\u6c27\u5316\u548cFe\u00b2\u207a\u84c4\u79ef\u88ab\u6291\u5236\uff0c\u540c\u65f6GSH\u542b\u91cf\u3001\u7ec6\u80de\u6d3b\u6027\u548c\u7ebf\u7c92\u4f53\u819c\u7535\u4f4d\u663e\u8457\u6062\u590d\uff08P<0.05\uff09\u3002\u800c\u4f7f\u7528Nutlin-3\u6fc0\u6d3bP53\u4fe1\u53f7\u901a\u8def\u540e\uff0c\u5929\u9ebb\u7d20\u7684\u4fdd\u62a4\u4f5c\u7528\u88ab\u660e\u663e\u9006\u8f6c\uff08P<0.05\uff09\u3002\u7ed3\u8bba: \u5929\u9ebb\u7d20\u53ef\u80fd\u901a\u8fc7\u8c03\u63a7P53/SLC7A11/GPX4\u4fe1\u53f7\u901a\u8def\u6291\u5236\u795e\u7ecf\u5143\u94c1\u6b7b\u4ea1\uff0c\u4ece\u800c\u5bf9\u9ad8\u539f\u4f4e\u538b\u7f3a\u6c27\u6027\u8111\u635f\u4f24\u53d1\u6325\u795e\u7ecf\u4fdd\u62a4\u4f5c\u7528\u3002.\n\nID: 42485981\nTitle: Cell death mechanisms in sepsis-associated adaptive immune dysfunction.\nAbstract: Sepsis remains a leading cause of death, driven not only by early hyperinflammation but also by a catastrophic collapse of adaptive immunity during the late phase. This failure is orchestrated by distinct regulated cell death (RCD) pathways - apoptosis, pyroptosis, necroptosis and ferroptosis - that differentially deplete T cells, B cells and dendritic cells while shaping the immunological milieu. Apoptosis silently eliminates lymphocytes and promotes immunosuppression; pyroptosis and necroptosis release damage-associated molecular patterns, fueling inflammation that paradoxically destroys adaptive effectors; and ferroptosis, an iron-dependent lipid peroxidation process, selectively targets metabolically active CD8+ and T helper cells. This review proposes that these pathways do not operate in isolation but converge on a \"cell death decision network\" centred on caspase-8, receptor-interacting serine/threonine-protein kinase 1(RIPK1), reactive oxygen species (ROS) and mitochondria, whose integration determines lymphocyte fate under septic stress. Understanding this network opens opportunities for precision immunotherapy. Emerging strategies targeting these pathways hold promise, but their success will require phase-specific application, biomarker-guided patient stratification and cell-type-selective delivery. Targeting the quality, as well as the quantity, of cell death may restore adaptive immunity and improve survival in sepsis.\n\nID: 42485915\nTitle: Stearoyl CoA desaturase 1 deficiency increases ferroptosis susceptibility in chicken embryonic liver cells.\nAbstract: Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation. It is increasingly recognized as a contributor to liver cell injury. Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme in monounsaturated fatty acid synthesis. It plays a key role in maintaining lipid homeostasis and may affect cellular susceptibility to ferroptosis. However, it remains unclear whether SCD1 restrains ferroptosis-associated injury in chicken embryonic liver (CEL) cells. Therefore, this study aimed to investigate the role of SCD1 in regulating ferroptosis susceptibility and cellular injury related to ferroptosis in CEL cells, with a focus on its effects on lipid metabolism, oxidative stress, and iron homeostasis. The results showed that SCD1 knockdown reduced intracellular lipid droplet area, triglyceride, and total cholesterol levels in CEL cells (P < 0.05). In addition, SCD1 knockdown induced mitochondrial ultrastructural changes associated with ferroptosis, including mitochondrial shrinkage, increased membrane density, and cristae disruption. It also aggravated oxidative stress, as shown by increased reactive oxygen species, oxidized glutathione, and malondialdehyde levels and decreased glutathione content (P < 0.05). SCD1 knockdown reduced cell viability, whereas oleic acid or ferrostatin-1 treatment partially reversed this decrease (P < 0.05). Moreover, SCD1 knockdown increased ACSL4 expression and decreased SLC7A11, GPX4, and Nrf2 expression at both the mRNA and protein levels (P < 0.05). SCD1 knockdown further reduced mitochondrial membrane potential and increased lipid peroxidation, intracellular Fe\u00b2\u207a levels, and total iron content (P < 0.05). In contrast, SCD1 overexpression increased lipid accumulation, reduced reactive oxygen species levels, increased glutathione content, increased SLC7A11, GPX4, and Nrf2 expression, and decreased ACSL4 protein expression (P < 0.05) without significantly affecting ACSL4 mRNA expression. These findings suggest that SCD1 regulates the susceptibility of CEL cells to ferroptosis and exerts a protective effect by improving lipid metabolism, antioxidant defenses, and mitochondrial function, indicating that SCD1 is a key regulatory factor in maintaining the homeostasis and health of chicken liver.\n\nID: 42484789\nTitle: The METTL3/TRIM37 axis contributes to the progression of non-alcoholic fatty liver disease by promoting CAV1 degradation.\nAbstract: Caveolin-1 (CAV1), a principal structural component of caveolae, plays a pivotal role in the regulation of lipid metabolism, signal transduction, and cellular homeostasis. Dysregulation of CAV1 has been implicated in the pathogenesis of metabolic diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the precise molecular mechanisms responsible for CAV1 in NAFLD remain largely unclear. In vitro experiments were performed using THLE-3 or HepG2 cells treated with palmitic acid (PA) to establish a lipotoxic model. Quantitative real-time polymerase chain reaction was used to detect mRNA levels, whereas western blotting was performed to analyze protein expression. Cell viability, proliferation, apoptosis, and lipid deposition were assessed using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and Oil Red O staining, respectively. Ferroptosis was evaluated by measuring Fe2+ levels, malondialdehyde (MDA), superoxide dismutase (SOD), and lipid peroxidation. Molecular interactions, including ubiquitination, co-immunoprecipitation (Co-IP), methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays, were used to analyze the association among m6A methyltransferase-like 3 (METTL3), tripartite motif containing 37 (TRIM37) and CAV1. An in vivo NAFLD model was generated in mice fed a high-fat diet (HFD). In the animal study, liver injury and steatosis were visualized by hematoxylin and eosin (H&E) and Oil Red O staining. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as hepatic triglyceride (TG) and total cholesterol (TC) levels, were quantified to assess liver function and lipid accumulation. CAV1 expression was downregulated in blood samples of NAFLD patients. PA treatment significantly downregulated CAV1 expression, inhibited cell proliferation, increased apoptosis, and enhanced ferroptosis and lipid deposition; however, all of which were significantly reversed by CAV1 overexpression. Mechanistically, the E3 ubiquitin ligase TRIM37 was identified as a negative regulator of CAV1; TRIM37 was found to interact with CAV1 and promote its ubiquitination and degradation. Furthermore, METTL3 upregulated TRIM37 expression by binding to its mRNA transcript in an IGF2BP1-dependent manner, thereby enhancing TRIM37 mRNA stability. Knockdown of TRIM37 or METTL3 mitigated PA-induced cellular damage, but these protective effects were abolished by CAV1 silencing or TRIM37 overexpression, respectively. Consistent with the in vitro findings, in vivo experiments confirmed that CAV1 overexpression attenuated HFD-induced liver injury. This study unveils a novel METTL3/TRIM37/CAV1 regulatory axis that represents an important pathway contributing to NAFLD exacerbation. Restoring CAV1 expression represents a promising therapeutic strategy for NAFLD.\n\nID: 42484787\nTitle: PHLDA3 hypomethylation at the mercy of PTBP1-mediated DNMT3a decay prompts ferroptosis of cardiomyocytes to accelerate microvascular endothelial cell senescence following ischemia/reperfusion injury.\nAbstract: Myocardial ischemia-reperfusion (I/R) injury is a complex condition characterized by oxidative stress, inflammation, and mitochondrial dysfunction. Ferroptosis, an iron-dependent form of regulated cell death, plays a critical role in cardiomyocyte damage during I/R. Inhibiting ferroptosis has been shown to reduce myocardial injury and improve cardiac function, making it a promising therapeutic target for enhancing clinical outcomes. An in vivo I/R model was established, and infarct size was assessed using triphenyltetrazolium chloride (TTC) staining. Histological changes were analyzed using hematoxylin and eosin (H&E) staining, Masson, immunohistochemistry (IHC), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Cellular experiments included analyses of reactive oxygen species (ROS), lipid peroxidation, and iron content using specific fluorescent probes, as well as enzymatic markers measured with commercial assay kits. Cell viability and senescence were evaluated using the Cell Counting Kit-8 (CCK-8) assay and senescence-associated \u03b2-galactosidase (SA-\u03b2-gal) staining, respectively. Mitochondrial ultrastructure was examined using transmission electron microscopy (TEM), while molecular mechanisms, including DNA methylation, were investigated using methylation-specific polymerase chain reaction (MSP). Interactions among pleckstrin homology-like domain family A member 3 (PHLDA3), DNA (cytosine-5)-methyltransferase 3\u00a0A (DNMT3a), and polypyrimidine tract binding protein 1 (PTBP1) were evaluated using chromatin immunoprecipitation (ChIP) and RNA pull-down assays. Silencing of PHLDA3 demonstrated protective effects against I/R injury by attenuating cardiomyocyte ferroptosis and cardiac microvascular endothelial cells (CMECs) senescence under hypoxia/reoxygenation (H/R) conditions in vitro and I/R injury in vivo. Mechanistically, downregulated DNMT3a was responsible for PHLDA3 hypomethylation. Furthermore, PTBP1 was identified as an upstream RNA-binding protein that destabilized DNMT3a mRNA during H/R injury, indirectly enhancing PHLDA3 expression. Our findings suggest that PTBP1-mediated DNMT3a downregulation contributes to PHLDA3 hypomethylation, which may promote cardiomyocyte ferroptosis and subsequent microvascular endothelial cell senescence during I/R injury.\n\nID: 42483586\nTitle: Mild Sulfidation Aggravates the Dissolution and Cytotoxicity of Silver Nanoparticles in Mammalian Cells.\nAbstract: Silver nanoparticles (Ag NPs) have been extensively utilized in food preservation, disinfection, personal care, and medical applications. Upon exposure to biological environments, pristine Ag NPs are susceptible to transformation into other chemical forms through processes, such as sulfidation. Although the majority of published literature indicates that sulfidation can significantly mitigate the toxicity of Ag NPs, it remains unknown how the degree of sulfidation influences nano-bio interactions of Ag NPs in mammalian cells. To elucidate the potential role of sulfidation in the cytotoxicity of Ag NPs, we first synthesized and characterized Ag NPs with varying degrees of sulfidation. Unexpectedly, while high-degree sulfidation resulted in a reduction of the cytotoxicity of Ag NPs, mild sulfidation intensified their toxicity. Further mechanistic investigations revealed that the oxidative dissolution of low-degree sulfidized Ag NPs enhanced the release of Ag+, promoted the generation of reactive oxygen radicals, and aggravated lipid peroxidation within cells, thereby activating ferroptosis through inhibiting the expression of ferritin and glutathione peroxidase 4.\n\nID: 42483464\nTitle: Biochanin A attenuates doxorubicin-induced cardiotoxicity in rats with associated modulation of PI3K/Akt/mTOR and p38 MAPK signaling.\nAbstract: Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity associated with oxidative stress, inflammation, and apoptosis. Biochanin A (BCA), an O-methylated isoflavone, has demonstrated antioxidant and anti-inflammatory properties. This study investigated whether BCA could mitigate DOX-induced cardiac injury in rats and explored the underlying molecular mechanisms. Male Wistar rats were randomly assigned to control, BCA-alone, DOX-alone, and DOX combined with BCA (25 or 50\u2005mg/kg) groups. Cardiotoxicity was induced by DOX administration. Electrocardiographic (ECG) parameters were recorded, and serum cardiac biomarkers (CK-MB, LDH, and troponin) were measured. Cardiac tissue was evaluated for oxidative stress markers, antioxidant enzyme activities, inflammatory mediators, and apoptotic gene expression. Histopathological examination was performed. The involvement of PI3K/Akt/mTOR, p38 MAPK, and PTEN signaling pathways was assessed using molecular analyses. DOX administration caused significant ECG abnormalities, elevated serum cardiac biomarkers, increased lipid peroxidation, reduced antioxidant enzyme activities, enhanced inflammatory cytokine levels, and upregulated pro-apoptotic markers in cardiac tissue. Histological examination revealed marked myocardial degeneration. BCA treatment attenuated these alterations, with greater effects observed at the higher dose in several endpoints. It was associated with improved antioxidant status, reduced inflammatory and apoptotic marker expression, decreased p38 MAPK and PTEN immunoreactivity, and was associated with altered PI3K/Akt/mTOR and p38 MAPK pathway-marker immunoreactivity compared with the DOX group. Biochanin A alleviated acute DOX-induced cardiotoxicity in rats and was associated with modulation of oxidative stress, inflammatory, apoptotic markers, as well as, PI3K/Akt/mTOR and p38 MAPK pathway markers. BCA may therefore represent a potential cardioprotective adjunct strategy in acute anthracycline-associated cardiac injury.\n\nID: 42483214\nTitle: Diquat-induced organ toxicity: a focus on regulated cell death pathways and mitochondrial dysfunction.\nAbstract: Diquat (1,1'-ethylene-2,2'-bipyridyl, DQ) is a herbicide widely used for weed control in both agricultural and non-cultivated areas. Although its acute toxicity is lower than that of paraquat, its high-water solubility and stability in acidic and neutral environments contribute to its prolonged environmental persistence. As DQ gradually replaces paraquat in agricultural practice, the incidence of DQ poisoning has increased significantly. DQ poisoning typically results from accidental ingestion, suicidal intake, or improper agricultural handling. To date, no specific antidote is available, and the high mortality associated with DQ poisoning presents a critical challenge for clinical management. Accumulating evidence indicates that the toxicity of DQ is primarily attributed to its capacity to generate reactive oxygen species (ROS), leading to oxidative stress and subsequent oxidative damage to lipids, proteins, and DNA, ultimately resulting in multi-organ dysfunction, with the kidneys and intestines being the primary target organs. The pathogenesis of DQ poisoning involves multiple factors, including oxidative stress imbalance, regulated cell death, mitochondrial dysfunction, and disturbances in energy metabolism. This review systematically examines the physicochemical properties, metabolic characteristics, biodistribution, and target organ toxicity of DQ, with a particular focus on the interplay between excessive ROS production and mitochondrial dysfunction in the context of oxidative stress. Furthermore, we provide an in-depth discussion on the roles of regulated cell death-including pyroptosis, ferroptosis, and mitophagy-and metabolic dysregulation in DQ-induced toxicity. In addition, this review summarizes the classical signaling pathways involved in organ dysfunction, current therapeutic strategies, and potential intervention targets, thereby offering a theoretical framework and future research directions for the management of DQ poisoning.\n\nID: 42482498\nTitle: NIR-II Type I AIE Photosensitiser-Functionalized MOF-Cu Nanoplatform Promotes Ferroptosis and Cuproptosis for Antitumor Therapy.\nAbstract: Cancer therapeutic strategies centered on synergistic ferroptosis and cuproptosis have attracted considerable interest. However, current approaches predominantly relying on Fe and Cu sources face limitations including single mode of reactive oxygen species (ROS) production, poor organelle targeting, and lack of imaging capabilities. Herein, we developed a multifunctional nanoplatform, NMC NPs, by integrating a type I aggregation-induced emission photosensitizer (NTI) with a Cu-based nanozyme (MOF-Cu). This design enables efficient ROS generation, precise mitochondria targeting, and real-time fluorescence imaging, allowing more effective activation of ferroptosis and cuproptosis. Upon cellular uptake, MOF-Cu framework dissociates and releases NTI, which selectively accumulates in mitochondria. Under 635\u00a0nm laser irradiation, NTI generates type I ROS, triggering lipid peroxidation and activating ferroptosis. Simultaneously, MOF-Cu nanozyme exerts dual peroxidase-like and glutathione peroxidase-like activities, catalyzing H2O2 into hydroxyl radicals while depleting glutathione and releasing Cu+ ions, further promoting ferroptosis. Notably, the released Cu+ ions further disrupt mitochondrial function, induce dihydrolipoamide S-acetyltransferase aggregation, and activate cuproptosis. The synergistic action efficiently enhances immunogenic cell death. In vivo studies confirmed the potent antitumor efficacy of NMC NPs with minimal side effect. This study provides new insights into the cooperative regulation of metal-dependent cell death and advances the design of integrated theranostic nanoplatforms.\n\nID: 41887951\nTitle: Repair condensates and lipid domains in lysosome integrity.\nAbstract: Lysosomes are sophisticated signaling hubs whose function depends on membrane integrity. A breach of this barrier, known as lysosomal membrane permeabilization, triggers inflammation and cell death, driving pathologies from lysosomal storage disorders to neurodegeneration. Cells counter membrane damage with diverse repair mechanisms, including endosomal sorting complexes required for transport machinery, sphingomyelin scrambling, annexin-mediated scaffolding, lipid transport, and stress granule plugging. This diversity suggests singular strategies are insufficient, posing an 'orchestration challenge' regarding precise initiation, spatial organization, and temporal coordination. This opinion article proposes that biomolecular condensation, initiated by damage cues, acts as a primary organizing principle. We suggest lysosomal injury nucleates de novo 'repair condensates' that stabilize compromised membranes and serve as recruitment and organizational hubs for repair machinery.\n\nID: 41622607\nTitle: Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP+ Model of Parkinson's Disease.\nAbstract: Dysregulation of autophagy and lysosomal function is central to Parkinson's disease (PD), yet the upstream mechanisms leading to lysosomal failure remain unclear. Across primary mouse cortical neurons, MT-3 deficient primary mouse astrocytes, human iPSC-derived midbrain dopaminergic neurons, and Rho0 CHO cells lacking mitochondrial respiration, we investigated how mitochondrial stress perturbs zinc (Zn2+) homeostasis and lysosomal integrity. We identify intracellular zinc as a critical mediator linking mitochondrial dysfunction to lysosomal membrane permeabilization (LMP) and neuronal death. Inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP+) elevated reactive oxygen species (ROS) and intracellular zinc, jointly driving LMP. Blocking either ROS or zinc markedly attenuated lysosomal damage and cell death, demonstrating that both act upstream of LMP. To define zinc regulation, we examined metallothionein-3 (MT-3), a brain-enriched zinc-binding protein. MT-3-deficient astrocytes were more vulnerable to MPP+ and zinc overload (ZnCl2) but paradoxically resistant to hydrogen peroxide (H2O2), suggesting that MT-3 buffers cytosolic zinc during mitochondrial injury or extracellular zinc influx yet can release bound zinc under oxidative conditions. Using Rho0 cells, we show that MPP+ toxicity depends on mitochondrial ROS, as loss of mitochondrial function nearly abolished cell death. However, Rho0 cells were highly sensitive to ZnCl2 and H2O2 and exhibited markedly reduced lysosomal abundance, indicating limited capacity to sequester zinc and increased susceptibility to zinc-mediated injury. These findings support a coordinated system in which lysosomes and zinc-binding proteins maintain zinc homeostasis. When cytosolic zinc rises, its accumulation within lysosomes induces LMP and accelerates cell death. Collectively, our results identify intracellular zinc as an upstream trigger of lysosomal dysfunction and neurodegeneration. Zinc-mediated LMP provides a mechanistic link between mitochondrial injury, impaired autophagic flux, and \u03b1-synuclein pathology in PD. Enhancing zinc homeostasis and lysosomal resilience may offer promising therapeutic strategies.\n\nID: 40349217\nTitle: Lysosomal Repair in Health and Disease.\nAbstract: Lysosomes are essential organelles degrading a wide range of substrates, maintaining cellular homeostasis, and regulating cell growth through nutrient and metabolic signaling. A key vulnerability of lysosomes is their membrane permeabilization (LMP), a process tightly linked to diseases including aging, neurodegeneration, lysosomal storage disorders, and cardiovascular disease. Research progress in the past few years has greatly improved our understanding of lysosomal repair mechanisms. Upon LMP, cells activate multiple membrane remodeling processes to restore lysosomal integrity, such as membrane invagination, tubulation, lipid patching, and membrane stabilization. These repair pathways are critical in preserving cellular stress tolerance and preventing deleterious inflammation and cell death triggered by lysosomal damage. This review focuses on the expanding mechanistic insights of lysosomal repair, highlighting its crucial role in maintaining cellular health and the implications for disease pathogenesis and therapeutic strategies.\n\nID: 38890703\nTitle: Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration.\nAbstract: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.\n\nID: 38594929\nTitle: The Endo-Lysosomal Damage Response.\nAbstract: Lysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the integrity of the lysosomal membrane. If repair fails or if damage is too extensive, lysosomes are isolated and degraded by a form of selective autophagy termed lysophagy. Meanwhile, an mTORC1-governed signaling cascade drives biogenesis and regeneration of new lysosomal components to reestablish the full lysosomal capacity of the cell. This damage response is vital to counteract the effects of various conditions, including neurodegeneration and infection, and can constitute a critical vulnerability in cancer cells.\n\nID: 31296844\nTitle: cPLA2 activation contributes to lysosomal defects leading to impairment of autophagy after spinal cord injury.\nAbstract: The autophagy-lysosomal pathway plays an essential role in cellular homeostasis as well as a protective function against a variety of diseases including neurodegeneration. Conversely, inhibition of autophagy, for example due to lysosomal dysfunction, can lead to pathological accumulation of dysfunctional autophagosomes and consequent neuronal cell death. We previously reported that autophagy is inhibited and contributes to neuronal cell death following spinal cord injury (SCI). In this study, we examined lysosomal function and explored the mechanism of lysosomal defects following SCI. Our data demonstrated that expression levels and processing of the lysosomal enzyme cathepsin D (CTSD) are decreased by 2\u2009h after SCI. Enzymatic activity levels of CTSD and another lysosomal enzyme, N-acetyl-alpha-glucosaminidase, are both decreased 24\u2009h post injury, indicating general lysosomal dysfunction. Subcellular fractionation and immunohistochemistry analysis demonstrated that this dysfunction is due to lysosomal membrane permeabilization and leakage of lysosomal contents into the cytosol. To directly assess extent and mechanisms of damage to lysosomal membranes, we performed mass spectrometry-based lipidomic analysis of lysosomes purified from SCI and control spinal cord. At 2\u2009h post injury our data demonstrated increase in several classes of lysosophospholipids, the products of phospholipases (PLAs), as well as accumulation of PLA activators, ceramides. Phospholipase cPLA2, the main PLA species expressed in the CNS, has been previously implicated in mediation of secondary injury after SCI, but the mechanisms of its involvement remain unclear. Our data demonstrate that cPLA2 is activated within 2\u2009h after SCI preferentially in the lysosomal fraction, where it colocalizes with lysosomal-associated membrane protein 2 in neurons. Inhibition of cPLA2 in vivo decreased lysosomal damage, restored autophagy flux, and reduced neuronal cell damage. Taken together our data implicate lysosomal defects in pathophysiology of SCI and for the first time indicate that cPLA2 activation leads to lysosomal damage causing neuronal autophagosome accumulation associated with neuronal cell death.\n\nID: 31238788\nTitle: PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma.\nAbstract: Lysosomal membrane permeabilization (LMP) is observed under many pathological conditions, leading to cellular dysfunction and death. However, the mechanisms by which lysosomal membranes become leaky in vivo are not clear. Our data demonstrate that LMP occurs in neurons following controlled cortical impact induced (CCI) traumatic brain injury (TBI) in mice, leading to impaired macroautophagy (autophagy) and neuronal cell death. Comparison of LC-MS/MS lysosomal membrane lipid profiles from TBI and sham animals suggested a role for PLA2G4A/cPLA2 (phospholipase A2, group IVA [cytosolic, calcium-dependent]) in TBI-induced LMP. Activation of PLA2G4A caused LMP and inhibition of autophagy flux in cell lines and primary neurons. In vivo pharmacological inhibition of PLA2G4A attenuated TBI-induced LMP, as well as subsequent impairment of autophagy and neuronal loss, and was associated with improved neurological outcomes. Inhibition of PLA2G4A in vitro limited amyloid-\u03b2-induced LMP and inhibition of autophagy. Together, our data indicate that PLA2G4A -mediated lysosomal membrane damage is involved in neuronal cell death following CCI-induced TBI and potentially in other neurodegenerative disorders.Abbreviations: AACOCF3, arachidonyl trifluoromethyl ketone; ACTB/\u03b2-actin, actin, beta; AD, Alzheimer disease; ATG5, autophagy related 5; ATG7, autophagy related 7; ATG12, autophagy related 12; BECN1, beclin 1, autophagy related; C1P, ceramide-1-phosphate; CCI, controlled cortical impact; CTSD, cathepsin D; CTSL, cathepsin L; GFP, green fluorescent protein; IF, immunofluorescence; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LMP, Lysosomal membrane permeabilization; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; MAP1LC3/LC3, microtuble-associated protein 1 light chain 3; NAGLU, alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); PC, diacyl glycerophosphatidylcholine; PE, diacyl glycerophosphatidylethanolamine; PE-O, plasmanyl glycerophosphatidylethanolamine; PE-P, plasmenyl glycerophosphatidylethanolamine; PLA2G4A/cPLA2, phospholipase A2, group IVA (cytosolic, calcium-dependent); RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3; RFP, red fluorescent protein; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TUBA1/\u03b1-tubulin, tubulin, alpha; TBI, traumatic brain injury; TFEB, transcription factor EB; ULK1, unc-51 like kinase 1.\n\nID: 28487766\nTitle: Malathion increases apoptotic cell death by inducing lysosomal membrane permeabilization in N2a neuroblastoma cells: a model for neurodegeneration in Alzheimer's disease.\nAbstract: Malathion is an organophosphate with severe neurotoxic effects. Upon acute exposure, malathion initially enhances cholinergic activity by inhibition of acetylcholinesterase, which is its major pathological mechanism. Malathion also induces non-cholinergic neuronal cell death in neurodegenerative conditions; the associated molecular mechanism is not well-characterized. To investigate the molecular mechanism of malathion-induced cell death, N2a mouse neuroblastoma cells were exposed to malathion and cell death-related parameters were examined. Malathion reduced cell viability mainly by apoptosis through mitochondrial dysfunction in N2a cells, as judged by an increase in the level of the pro-apoptotic protein Bax and decrease in the levels of the anti-apoptotic proteins p-Akt and Bcl2, resulting in cytochrome c release and caspase-dependent DNA fragmentation and condensation. Malathion treatment also induced autophagy and lysosomal membrane permeabilization (LMP) in N2a cells. LMP caused a lessening of autophagic flux via inhibition of lysosomal fusion with the autophagosome. LMP-induced cathepsin B release and its proteolytic effect may intensify apoptotic insults. Moreover, malathion-exposed N2a cells showed a marked reduction in the levels of the neuronal marker proteins vascular endothelial growth factor and heart fatty acid binding protein 3, along with diminished neuritogenesis in N2a cells and nerve growth factor secretion in C6 glioma cells. Our data suggest that the non-cholinergic effect of malathion may be mediated by apoptotic cell death via LMP induction in N2a cells. Malathion-treated N2a cells can be utilized as an in vitro model system to screen natural and new chemical drug candidates for neurodegenerative diseases such as Alzheimer's disease.\n\nID: 27753622\nTitle: VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy.\nAbstract: Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation. Lysosomal clearance is also compromised in MEFs harboring a p97 mutation that causes inclusion body myopathy and neurodegeneration, and damaged lysosomes accumulate in affected patient tissue carrying the mutation. Moreover, we show that p97 helps clear late endosomes/lysosomes ruptured by endocytosed tau fibrils. Thus, our data reveal an important mechanism of how p97 maintains lysosomal homeostasis, and implicate the pathway as a modulator of degenerative diseases.\n\nID: 26908626\nTitle: Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.\nAbstract: Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease.\n\nID: 25637183\nTitle: Glycosphingolipids and cell death: one aim, many ways.\nAbstract: Glycosphingolipids (GSLs) are a family of bioactive lipids that in addition to their role in the regulation of structural properties of membrane bilayers have emerged as crucial players in many biological processes and signal transduction pathways. Rather than being uniformly distributed within membrane bilayers, GSLs are localized in selective domains called lipid rafts where many signaling platforms operate. One of the most important functions of GSLs, particularly ceramide, is their ability to regulate cell death pathways and hence cell fate. This complex role is accomplished by the ability of GSLs to act in distinct subcellular strategic centers, such as mitochondria, endoplasmic reticulum (ER) or lysosomes to mediate apoptosis, ER stress, autophagy, lysosomal membrane permeabilization and necroptosis. Hence better understanding the role of GSLs in cell death may be of relevance for a number of pathological processes and diseases, including neurodegeneration, metabolic liver diseases and cancer.\n\nID: 24837749\nTitle: Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities.\nAbstract: Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition. The critical role of lysosomal functionality is evident from the severity of the diseases in which the primary lesion is a genetically defined loss-of-function of lysosomal hydrolases or membrane proteins. This group of diseases, known as lysosomal storage diseases (LSDs), number more than 50 and are associated with severe neurodegeneration, systemic disease, and early death, with only a handful of the diseases having a therapeutic option. Another key homeostatic system is the metabolic stress response or heat shock response (HSR), which is induced in response to a number of physiological and pathological stresses, such as protein misfolding and aggregation, endoplasmic reticulum stress, oxidative stress, nutrient deprivation, elevated temperature, viral infections, and various acute traumas. Importantly, the HSR and its cardinal members of the heat shock protein 70 family has been shown to protect against a number of degenerative diseases, including severe diseases of the nervous system. The cytoprotective actions of the HSR also include processes involving the lysosomal system, such as cell death, autophagy, and protection against lysosomal membrane permeabilization, and have shown promise in a number of LSDs. This review seeks to describe the emerging understanding of the interplay between these two essential metabolic systems, the lysosomes and the HSR, with a particular focus on their potential as a therapeutic target for LSDs.\n\nID: 24488099\nTitle: High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A.\nAbstract: Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"lmp_death_switch\": Investigate if lysosomal rupture (LMP) serves as the common upstream temporal initiator for both karyoptosis and ferroptosis in motor neuron models.\n- \"p38_lipid_link\": Examine whether the p38 kinase/LaminB1 signaling axis, which governs karyoptosis, also regulates the expression or activity of ferroptosis-related proteins like GPX4 or ACSL4.\n- \"polypharmacy_validation\": Determine if simultaneous pharmacological blockade of p38 kinase and enhancement of lipid peroxidation scavenging provides synergistic rescue of motor neuron viability compared to monotherapy.\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42365390\nTitle: Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.\nAbstract: Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression. To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent \"prion-like\" spreading of aggregates. The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival. Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.\n\nID: 42327061\nTitle: Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.\nAbstract: Lysosomal membrane damage triggers a multi-stage repair response essential for cellular homeostasis. Here we identify the oxysterol-binding protein-related protein ORP3 as a critical mediator of late-stage lysosomal membrane repair. Following lysosomal damage induced by L-leucine-leucine methyl ester (LLOME) or cationic amphiphilic drugs (CADs), ORP3 is phosphorylated and recruited to ER-lysophagosome contact sites via a signaling cascade initiated by lysosomal membrane ubiquitination, TAK1, p38 MAPK, and, to a lesser extent, IKK. p38-dependent phosphorylation promotes direct interaction between ORP3 and LC3B, which together with PI(4,5)P\u2082 binding, is required for autophagic lysosome recruitment. ORP3 depletion impairs late-stage lysosomal recovery, elevates lysosomal lipid peroxidation, and reduces cell survival. A lipid transfer-deficient ORP3 mutant fails to restore lysosome function despite normal recruitment, indicating that ER-to-lysophagosome transfer of phosphatidylcholine by ORP3 is functionally required. ORP3 activity is subsequently terminated by VCP/p97-mediated deubiquitination of lysosomes. These findings define ORP3 as a MAPK regulated lipid transfer protein during the late autophagic phase of the endolysosomal damage response. Lysosomal membrane damage triggers ubiquitination that activates a TAK1-p38 signaling cascade, phosphorylating the lipid transfer protein ORP3 and recruiting it to damaged lysosomes via LC3B interaction. ORP3-mediated phosphatidylcholine transfer from the ER is essential for late-stage lysosomal repair and cell survival.\n\nID: 42012504\nTitle: SLC25A21 promotes ferroptosis by inducing mitochondrial GPX4 deficiency in colorectal cancer.\nAbstract: Mitochondrial 2-oxodicarboxylate carrier (SLC25A21) plays a crucial role in maintaining mitochondrial function and regulating apoptosis. Whether SLC25A21 influences cell death solely through apoptosis remains unclear. Here, we reported that mitochondrial protein Methylcrotonoyl-CoA carboxylase beta chain (MCCC2) co-localized with mitochondrial inner membrane protein SLC25A21 and promoted its lysosomal degradation in colorectal cancer (CRC) cells. The ectopic overexpression of SLC25A21 significantly inhibited the malignant behaviors of CRC cells. Overexpression of SLC25A21 induced cell death and cell cycle arrest at the G2/M phase, and triggered hallmark ferroptotic alterations, including lipid peroxidation (LPO) and reactive oxygen species (ROS) accumulation, increased Malondialdehyde (MDA) contents, GSSG/GSH and NADP\u2009+\u2009/NADPH ratios, and abnormal mitochondrial morphologies. Mechanistically, SLC25A21 formed a complex with Glutathione Peroxidase 4 (GPX4) and activated the MEK-ERK and p38 MAPK signaling pathways, together reducing the GPX4 pool in mitochondria. Treatment of CRC cells with a GPX4 agonist inhibited SLC25A21-induced ferroptosis, thereby reducing the production of LPO and ROS, and restoring partially malignant behaviors of the cells. In vivo, SLC25A21 inhibited tumor growth by activating ferroptosis. Relatively high expression of SLC25A21 was associated with unfavorable outcomes in multiple patient cohorts, suggesting a complex role for SLC25A21 in CRC progression. Together, we identified SLC25A21-GPX4 interaction as an important regulatory axis in mitochondrial redox maintenance.\n\nID: 39602452\nTitle: Coronavirus nucleocapsid protein enhances the binding of p-PKC\u03b1 to RACK1: Implications for inhibition of nucleocytoplasmic trafficking and suppression of the innate immune response.\nAbstract: The hallmark of coronavirus infection lies in its ability to evade host immune defenses, a process intricately linked to the nuclear entry of transcription factors crucial for initiating the expression of antiviral genes. Central to this evasion strategy is the manipulation of the nucleocytoplasmic trafficking system, which serves as an effective target for the virus to modulate the expression of immune response-related genes. In this investigation, we discovered that infection with the infectious bronchitis virus (IBV) dynamically impedes the nuclear translocation of several transcription factors such as IRF3, STAT1, STAT2, NF-\u03baB p65, and the p38 MAPK, leading to compromised transcriptional induction of key antiviral genes such as IFN\u03b2, IFITM3, and IL-8. Further examination revealed that during the infection process, components of the nuclear pore complex (NPC), particularly FG-Nups (such as NUP62, NUP153, NUP42, and TPR), undergo cytosolic dispersion from the nuclear envelope; NUP62 undergoes phosphorylation, and NUP42 exhibits a mobility shift in size. These observations suggest a disruption in nucleocytoplasmic trafficking. Screening efforts identified the IBV nucleocapsid (N) protein as the agent responsible for the cytoplasmic distribution of FG-Nups, subsequently hindering the nuclear entry of transcription factors and suppressing the expression of antiviral genes. Interactome analysis further revealed that the IBV N protein interacts with the scaffold protein RACK1, facilitating the recruitment of activated protein kinase C alpha (p-PKC\u03b1) to RACK1 and relocating the p-PKC\u03b1-RACK1 complex to the cytoplasm. These observations are conserved across diverse coronaviruses N proteins. Concurrently, the presence of both RACK1 and PKC\u03b1/\u03b2 proved essential for the phosphorylation and cytoplasmic dispersion of NUP62, the suppression of antiviral cytokine expression, and efficient virus replication. These findings unveil a novel, highly effective, and evolutionarily conserved mechanism.\n\nID: 39541976\nTitle: Lysosomal damage triggers a p38 MAPK-dependent phosphorylation cascade to promote lysophagy via the small heat shock protein HSP27.\nAbstract: Maintenance of lysosomal integrity is essential for cell viability. Upon injury, lysosomes may be targeted for degradation via a selective form of autophagy known as lysophagy. The engulfment of a damaged lysosome by an autophagosome is mediated by the recruitment of adaptor proteins, including SQSTM1/p62. p62 promotes lysophagy via the formation of phase-separated condensates in a mechanism that is regulated by the heat shock protein HSP27. Here, we demonstrate a direct interaction between HSP27 and p62. We used structural modeling to predict the binding interface between HSP27 and p62 and identify several disease-associated mutations that map to this interface. We used proteomics to identify post-translational modifications of HSP27 that regulate HSP27 recruitment to stressed lysosomes, finding robust phosphorylation at several serine residues. Next, we characterized the upstream signaling mechanism leading to HSP27 phosphorylation and found that p38 mitogen-activated protein kinase (MAPK) and its effector kinase MAP kinase-activated protein kinase 2 (MK2) are activated upon lysosomal damage by the kinase mTOR and the production of intracellular reactive oxygen species (ROS). Increased ROS activates p38 MAPK, which in turn allows MK2-dependent phosphorylation of HSP27. Depletion of HSP27 or the inhibition of HSP27 phosphorylation alters the dynamics of p62 condensates on stressed lysosomes, significantly inhibiting p62-dependent lysophagy. Thus, we define a novel lysosomal quality control mechanism in which lysosomal injury triggers a p38 MAPK/MK2 signaling cascade promoting p62-dependent lysophagy. Further, this signaling cascade is activated by many cellular stressors, including oxidative and heat stress, suggesting that other forms of selective autophagy may be regulated by p38 MAPK/MK2/HSP27.\n\nID: 38827785\nTitle: Deguelin Restores Paclitaxel Sensitivity in Paclitaxel-Resistant Ovarian Cancer Cells via Inhibition of the EGFR Signaling Pathway.\nAbstract: Ovarian cancer is one of women's malignancies with the highest mortality among gynecological cancers. Paclitaxel is used in first-line ovarian cancer chemotherapy. Research on paclitaxel-resistant ovarian cancer holds significant clinical importance. Cell viability and flow cytometric assays were conducted at different time and concentration points of deguelin and paclitaxel treatment. Immunoblotting was performed to assess the activation status of key signaling molecules important for cell survival and proliferation following treatment with deguelin and paclitaxel. The fluo-3 acetoxymethyl assay for P-glycoprotein transport activity assay and cell viability assay in the presence of N-acetyl-L-cysteine were also conducted. Cell viability and flow cytometric assays demonstrated that deguelin resensitized paclitaxel in a dose- and time-dependent manner. Cotreatment with deguelin and paclitaxel inhibited EGFR and its downstream signaling molecules, including AKT, ERK, STAT3, and p38 MAPK, in SKOV3-TR cells. Interestingly, cotreatment with deguelin and paclitaxel suppressed the expression level of EGFR via the lysosomal degradation pathway. Cotreatment did not affect the expression and function of P-glycoprotein. N-acetyl-L-cysteine failed to restore cell cytotoxicity when used in combination with deguelin and paclitaxel in SKOV3-TR cells. The expression of BCL-2, MCL-1, and the phosphorylation of the S155 residue of BAD were downregulated. Moreover, inhibition of paclitaxel resistance by deguelin was also observed in HeyA8-MDR cells. Our research showed that deguelin effectively suppresses paclitaxel resistance in SKOV3-TR ovarian cancer cells by downregulating the EGFR and its downstream signaling pathway and modulating the BCL-2 family proteins. Furthermore, deguelin exhibits inhibitory effects on paclitaxel resistance in HeyA8-MDR ovarian cancer cells, suggesting a potential mechanism for paclitaxel resensitization that may not be cell-specific. These findings suggest that deguelin holds promise as an anticancer therapeutic agent for overcoming chemoresistance in ovarian cancer.\n\nID: 37033323\nTitle: LAMP5 may promote MM progression by activating p38.\nAbstract: Multiple myeloma (MM) is the second most common tumor of the hematologic system. MM remains incurable at this time. In this study, we used bioinformatics analysis to find key genes in the pathogenesis of MM. We first found that Lysosome associated membrane protein 5 (LAMP5) expression was sequentially increased in healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and newly diagnosed MM (NDMM), relapsed MM (RMM). We collected bone marrow from patients with NDMM, HD and post-treatment MM (PTMM) and performed qPCR analysis of LAMP5, and found that the expression of LAMP5 is stronger in NDMM than in HD, and decreases after treatment. Western blotting assay also found more expression of LAMP5 in NDMM than in HD. Patients with high LAMP5 expression have a higher DS (Durie-Salmon) stage and worse prognosis. We next verified the expression of LAMP5 in four MM cell lines and silenced LAMP5 expression in RPMI-8226 and AMO-1, and explored the effects of LAMP5 silencing on MM cell apoptosis and cell cycle by flow cytometry and western blotting. Knockdown of LAMP5 promoted apoptosis in MM cells, but had no effect on the cell cycle. Mechanistically, LAMP5 may exert its pro-tumor effects in MM in part through activation of p38 protein. We screened LAMP5 for the first time as a key gene for MM progression and recurrence, and found that LAMP5 may exert its pro-tumor effects in MM through activation of p38 protein.\n\nID: 36283391\nTitle: Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts.\nAbstract: Nuclear pores are essential for nuclear-cytoplasmic transport. Whether and how cells change nuclear pores to alter nuclear transport and cellular function is unknown. Here, we show that rat heart muscle cells (cardiomyocytes) undergo a 63% decrease in nuclear pore numbers during maturation, and this changes their responses to extracellular signals. The maturation-associated decline in nuclear pore numbers is associated with lower nuclear import of signaling proteins such as mitogen-activated protein kinase (MAPK). Experimental reduction of nuclear pore numbers decreased nuclear import of signaling proteins, resulting in decreased expression of immediate-early genes. In a mouse model of high blood pressure, reduction of nuclear pore numbers improved adverse heart remodeling and reduced progression to lethal heart failure. The decrease in nuclear pore numbers in cardiomyocyte maturation and resulting functional changes demonstrate how terminally differentiated cells permanently alter their handling of information flux across the nuclear envelope and, with that, their behavior.\n\nID: 35849032\nTitle: Hepatocyte-derived MASP1-enriched small extracellular vesicles activate HSCs to promote liver fibrosis.\nAbstract: Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. \u03b2-arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis. Normal and fibrotic human liver and serum samples were obtained. CCl 4 -induced liver fibrosis and methionine-choline deficiency-induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up-regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte-derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan-binding lectin serine protease 1 (MASP1) was enriched in hepatocyte-derived small EVs and activated HSCs via p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up-regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis. ARRB1 up-regulates the release of hepatocyte-derived MASP1-enriched small EVs by regulating the autophagic-lysosomal/multivesicular body pathway and Rab27A. Hepatocyte-derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.\n\nID: 35302183\nTitle: Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF-\u03b1 expression in hydroquinone-treated leukemia cells.\nAbstract: Our previous studies indicated that the benzene metabolite hydroquinone (HQ) evokes the ROS/p38 MAPK/protein phosphatase 2A/tristetraprolin axis, leading to increased TNF-\u03b1 expression in human acute myeloid leukemia cell lines U937 and HL-60. In this study, we aimed to identify the upstream pathway involved in ROS-mediated TNF-\u03b1 expression. HQ treatment increased SIDT2 expression, which subsequently decreased miR-25 and SIRT3 expression in U937 cells. Notably, miR-25 downregulation promoted SIDT2 expression in HQ-treated U937 cells. SIDT2 induced lysosomal degradation of SIRT3 mRNA, but inhibited miR-25 expression through a lysosome-independent pathway. MiR-25 inhibition reduced NOX4 mRNA turnover, resulting in increased NOX4 protein levels. NOX4 induces mitochondrial ROS production and HuR downregulation. Restoration of HuR expression increased SIRT3 expression, suggesting that NOX4-mediated HuR downregulation promotes SIDT2-mediated degradation of SIRT3 mRNA. Inhibition of NOX4 or SIRT3 overexpression abolished HQ-induced ROS production, thereby abolishing TNF-\u03b1 upregulation. Overall, these results indicate that SIDT2 regulates the miR-25/NOX4/HuR axis and SIRT3 mRNA destabilization, leading to ROS-mediated TNF-\u03b1 upregulation in HQ-treated U937 cells. HQ-induced increase in TNF-\u03b1 expression in HL-60 cells was also mediated through a similar pathway.\n\nID: 35219693\nTitle: Casein kinase I inhibitor D4476 influences autophagy and apoptosis in chloroquine-induced adult retinal pigment epithelial-19\u00a0cells.\nAbstract: The antimalarial drug chloroquine (CQ) induces retinopathy, a disorder characterized by lysosomotropic alteration. In this study, we examined whether D4476 (4-(4-(2,3-dihydrobenzo [1,4] dioxin-6-yl)-5-pyridin-2-yl-1H-imidazole-2-yl) benzamide), a specific casein kinase 1 inhibitor, alleviate CQ-induced retinopathy in adult retinal pigment epithelial (ARPE-19) cells. Cultured ARPE-19\u00a0cells were exposed to CQ with or without D4476 and cell death was quantified using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. To examine autophagy flux, ARPE-19\u00a0cells were transfected with green fluorescence protein light chain 3 (GFP-LC3)-red fluorescence protein (RFP)-LC3\u0394G plasmid DNA and co-stained with the lysosomal-associated membrane protein (LAMP)-1 antibody. Western blotting and fluorescence-activated cell sorting (FACS) showed apoptosis, whereas the fluorescence intensity of 2'-7'-dichlorofluorescein diacetate revealed levels of cellular oxidative stress. We then confirmed the effect of D4476 on the interaction between Beclin 1 and B-cell lymphoma-2 (Bcl-2) through immunoprecipitation with an anti-Bcl-2 antibody. Following CQ exposure, ARPE-19\u00a0cells accumulated autophagosomes because of defective lysosomal degradation. Furthermore, CQ trapped Beclin 1 with Bcl-2, disturbing autophagy initiation and autolysosome formation. However, D4476 alleviated CQ-induced effects by rescuing ARPE-19\u00a0cells from CQ-induced toxicity by modulating the association between Beclin 1 and Bcl-2. Therefore, D4476 controls autophagy and apoptosis simultaneously by upregulating autophagy flux, decreasing ROS formation, and triggering the expression of anti-apoptotic proteins through inhibition of mTOR, JNK, and p38 MAPK signals. We conclude that D4476 is a promising treatment strategy for CQ-mediated retinopathy.\n\nID: 34606852\nTitle: Regulatory mechanism of cyclins and cyclin-dependent kinases in post-mitotic neuronal cell division.\nAbstract: Neurodegenerative diseases (NDDs) are the most common life-threatening disease of the central nervous system and it cause the progressive loss of neuronal cells. The exact mechanism of the disease's progression is not clear and thus line of treatment for NDDs is a baffling issue. During the progression of NDDs, oxidative stress and DNA damage play an important regulatory function, and ultimately induces neurodegeneration. Recently, aberrant cell cycle events have been demonstrated in the progression of different NDDs. However, the pertinent role of signaling mechanism, for instance, post-translational modifications, oxidative stress, DNA damage response pathway, JNK/p38 MAPK, MEK/ERK cascade, actively participated in the aberrant cell cycle reentry induced neuronal cell death. Mounting evidence has demonstrated that aberrant cell cycle re-entry is a major contributing factor in the pathogenesis of NDDs rather than a secondary phenomenon. In the brain of AD patients with mild cognitive impairment, post miotic cell division can be seen in the early stage of the disease. However, in the brain of PD patients, response to various neurotoxic signals, the cell cycle re-entry has been observed that causes neuronal apoptosis. On contrary, the contributing factors that leads to the induction of cell cycle events in mature neurons in HD and ALS brain pathology is remain unclear. Various pharmacological drugs have been developed to reduce the pathogenesis of NDDs, but they are still not helpful in eliminating the cause of these NDDs.\n\nID: 34394034\nTitle: Staphylococcus aureus \u03b1-Toxin Induces Acid Sphingomyelinase Release From a Human Endothelial Cell Line.\nAbstract: Staphylococcus aureus (S. aureus) is well known to express a plethora of toxins of which the pore-forming hemolysin A (\u03b1-toxin) is the best-studied cytolysin. Pore-forming toxins (PFT) permeabilize host membranes during infection thereby causing concentration-dependent effects in host cell membranes ranging from disordered ion fluxes to cytolysis. Host cells possess defense mechanisms against PFT attack, resulting in endocytosis of the breached membrane area and delivery of repair vesicles to the insulted plasma membrane as well as a concurrent release of membrane repair enzymes. Since PFTs from several pathogens have been shown to recruit membrane repair components, we here investigated whether staphylococcal \u03b1-toxin is able to induce these mechanisms in endothelial cells. We show that S. aureus \u03b1-toxin induced increase in cytosolic Ca2+ in endothelial cells, which was accompanied by p38 MAPK phosphorylation. Toxin challenge led to increased endocytosis of an extracellular fluid phase marker as well as increased externalization of LAMP1-positive membranes suggesting that peripheral lysosomes are recruited to the insulted plasma membrane. We further observed that thereby the lysosomal protein acid sphingomyelinase (ASM) was released into the cell culture medium. Thus, our results show that staphylococcal \u03b1-toxin triggers mechanisms in endothelial cells, which have been implicated in membrane repair after damage of other cell types by different toxins.\n\nID: 33679663\nTitle: Structural and Signaling Events Driving Aspergillus fumigatus-Induced Human Eosinophil Extracellular Trap Release.\nAbstract: Eosinophils are granulocytes classically involved in allergic diseases and in the host immune responses to helminths, fungi, bacteria and viruses. The release of extracellular DNA traps by leukocytes is an important mechanism of the innate immune response to pathogens in various infectious conditions, including fungal infections. Aspergillus fumigatus is an opportunistic fungus responsible for allergic bronchopulmonary aspergillosis (ABPA), a pulmonary disease marked by prominent eosinophilic inflammation. Previously, we demonstrated that isolated human eosinophils release extracellular DNA traps (eosinophil extracellular traps; EETs) when stimulated by A. fumigatus in vitro. This release occurs through a lytic non-oxidative mechanism that involves CD11b and Syk tyrosine kinase. In this work, we unraveled different intracellular mechanisms that drive the release of extracellular DNA traps by A. fumigatus-stimulated eosinophils. Ultrastructurally, we originally observed that A. fumigatus-stimulated eosinophils present typical signs of extracellular DNA trap cell death (ETosis) with the nuclei losing both their shape (delobulation) and the euchromatin/heterochromatin distinction, followed by rupture of the nuclear envelope and EETs release. We also found that by targeting class I PI3K, and more specifically PI3K\u03b4, the release of extracellular DNA traps induced by A. fumigatus is inhibited. We also demonstrated that A. fumigatus-induced EETs release depends on the Src family, Akt, calcium and p38 MAPK signaling pathways in a process in which fungal viability is dispensable. Interestingly, we showed that A. fumigatus-induced EETs release occurs in a mechanism independent of PAD4 histone citrullination. These findings may contribute to a better understanding of the mechanisms that underlie EETs release in response to A. fumigatus, which may lead to better knowledge of ABPA pathophysiology and treatment.\n\nID: 31619537\nTitle: Mycobacterium tuberculosis LprE Suppresses TLR2-Dependent Cathelicidin and Autophagy Expression to Enhance Bacterial Survival in Macrophages.\nAbstract: Despite representing a very important class of virulence proteins, the role of lipoproteins in the pathogenesis of Mycobacterium tuberculosis remains elusive. In this study, we investigated the role of putative lipoprotein LprE in the subversion of host immune responses using the M. tuberculosis CDC1551 LprE (LprE Mtb ) mutant (Mtb\u2206LprE). We show that deletion of LprE Mtb results in reduction of M. tuberculosis virulence in human and mouse macrophages due to upregulation of vitamin D3-responsive cathelicidin expression through the TLR2-dependent p38-MAPK-CYP27B1-VDR signaling pathway. Conversely, episomal expression of LprE Mtb in Mycobacterium smegmatis improved bacterial survival. Infection in siTLR2-treated or tlr2-/- macrophages reduced the survival of LprE Mtb expressing M. tuberculosis and M. smegmatis because of a surge in the expression of cathelicidin. Infection with the LprE Mtb mutant also led to accumulation of autophagy-related proteins (LC3, Atg-5, and Beclin-1) and augmented recruitment of phagosomal (EEA1 and Rab7) and lysosomal (LAMP1) proteins, thereby resulting in the reduction of the bacterial count in macrophages. The inhibition of phago-lysosome fusion by LprE Mtb was found to be due to downregulation of IL-12 and IL-22 cytokines. Altogether, our data indicate that LprE Mtb is an important virulence factor that plays a crucial role in mycobacterial pathogenesis in the context of innate immunity.\n\nID: 31331032\nTitle: Roscovitine Attenuates Microglia Activation and Monocyte Infiltration via p38 MAPK Inhibition in the Rat Frontoparietal Cortex Following Status Epilepticus.\nAbstract: Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by brain-blood barrier. Following status epilepticus (SE, a prolonged seizure activity), microglia are rapidly activated and blood-derived monocytes that infiltrate the brain; therefore, the regulations of microglia activation and monocyte infiltration are one of the primary therapeutic strategies for inhibition of undesirable consequences from SE. Roscovitine, a potent (but not selective) cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models, although the underlying mechanisms have not been clarified. In the present study, roscovitine attenuated SE-induces monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC), accompanied by reducing expressions of monocyte chemotactic protein-1 (MCP-1) and lysosome-associated membrane protein 1 (LAMP1) in resident microglia, while it did not affect microglia transformation to amoeboid form. Furthermore, roscovitine ameliorated the up-regulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, but not nuclear factor-\u03baB-S276 phosphorylation. Similar to roscovitine, SB202190, a p38 MAPK inhibitor, mitigated monocyte infiltration and microglial expressions of MCP-1 and LAMP1 in the FPC following SE. Therefore, these findings suggest for the first time that roscovitine may inhibit SE-induced neuroinflammation via regulating p38 MAPK-mediated microglial responses.\n\nID: 30946556\nTitle: Beta-Like Importins Mediate the Nuclear Translocation of MAPKs.\nAbstract: The rapid nuclear translocation of signaling proteins upon stimulation is important for the regulation of de-novo gene expression. However, the molecular mechanisms of this translocation is not well understood, although some studies suggest that much of this translocation may be mediated by beta-like importins (Imps). Here we undertook to study the stimulated nuclear shuttling of JNK and p38 MAPKs. For this purpose, we used coimmunoprecipitation, proximity ligation assay, gel filtration and immunostaining to examine the mechanism of nuclear translocation of these proteins. We found that JNK and p38 MAPKs translocate into the nucleus in a Ran dependent, but NLS- or NTS-independent manner, unrelated to their catalytic activity. We show that this translocation involves three \u03b2-like Imps, 3, 7 and 9. Knockdown of these Imps inhibits the nuclear translocation of the MAPKs, and thereby, phosphorylation of their transcription factor targets. We further demonstrate that the translocation requires the stimulated formation of heterotrimers composed of Imp3/Imp7/MAPK or Imp3/Imp9/MAPK. JNK1/2 and p38\u03b1/\u03b2 bind to either Imp7 or Imp9 upon stimulated post-translational modifications of the two Imps, while Imp3 joins the complex after its stimulation-induced phosphorylation. Once formed, these heterotrimers move to the nuclear envelope where Imp3 remains, while Imp7 or Imp9 escort the MAPKs into the nucleus. These results suggest that \u03b2-like Imps are central mediators of stimulated nuclear translocation of signaling proteins, providing a central level of regulation of the induction of cellular processes such as transcription upon stimulation.\n\nID: 30842278\nTitle: A SIR-independent role for cohesin in subtelomeric silencing and organization.\nAbstract: Cohesin is a key determinant of chromosome architecture due to its DNA binding and tethering ability. Cohesin binds near centromeres and chromosome arms and also close to telomeres, but its role near telomeres remains elusive. In budding yeast, transcription within 20 kb of telomeres is repressed, in part by the histone-modifying silent information regulator (SIR) complex. However, extensive subtelomeric repressed domains lie outside the SIR-binding region, but the mechanism of silencing in these regions remains poorly understood. Here, we report a role for cohesin in subtelomeric silencing that extends even beyond the zone of SIR binding. Clusters of subtelomeric genes were preferentially derepressed in a cohesin mutant, whereas SIR binding was unaltered. Genetic interactions with known telomere silencing factors indicate that cohesin operates independent of the SIR-mediated pathway for telomeric silencing. Mutant cells exhibited Mpk1-dependent Sir3 hyperphosphorylation that contributes to subtelomeric derepression to a limited extent. Compaction of subtelomeric domains and tethering to the nuclear envelope were impaired in mutant cells. Our findings provide evidence for a unique SIR-independent mechanism of subtelomeric repression mediated by cohesin.\n\nID: 29789529\nTitle: Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1G93A mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer's disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1G93A motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPK\u03b1) was the sole isoform responsible for SOD1G93A-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPK\u03b1 inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1G93A mice. Our findings demonstrate the pathogenic effect of p38 MAPK\u03b1 on axonal retrograde transport and identify a potential therapeutic strategy for ALS.\n\nID: 29255092\nTitle: Ligand-activated epidermal growth factor receptor (EGFR) signaling governs endocytic trafficking of unliganded receptor monomers by non-canonical phosphorylation.\nAbstract: The canonical description of transmembrane receptor function is initial binding of ligand, followed by initiation of intracellular signaling and then internalization en route to degradation or recycling to the cell surface. It is known that low concentrations of extracellular ligand lead to a higher proportion of receptor that is recycled and that non-canonical mechanisms of receptor activation, including phosphorylation by the kinase p38, can induce internalization and recycling. However, no connections have been made between these pathways; i.e. it has yet to be established what happens to unbound receptors following stimulation with ligand. Here we demonstrate that a minimal level of activation of epidermal growth factor receptor (EGFR) tyrosine kinase by low levels of ligand is sufficient to fully activate downstream mitogen-activated protein kinase (MAPK) pathways, with most of the remaining unbound EGFR molecules being efficiently phosphorylated at intracellular serine/threonine residues by activated mitogen-activated protein kinase. This non-canonical, p38-mediated phosphorylation of the C-tail of EGFR, near Ser-1015, induces the clathrin-mediated endocytosis of the unliganded EGFR monomers, which occurs slightly later than the canonical endocytosis of ligand-bound EGFR dimers via tyrosine autophosphorylation. EGFR endocytosed via the non-canonical pathway is largely recycled back to the plasma membrane as functional receptors, whereas p38-independent populations are mainly sorted for lysosomal degradation. Moreover, ligand concentrations balance these endocytic trafficking pathways. These results demonstrate that ligand-activated EGFR signaling controls unliganded receptors through feedback phosphorylation, identifying a dual-mode regulation of the endocytic trafficking dynamics of EGFR.\n\nID: 29196611\nTitle: Cell signaling abnormalities in cardiomyopathy caused by lamin A/C gene mutations.\nAbstract: Mutations in the lamin A/C gene (LMNA) encoding intermediate filament proteins associated with the inner nuclear membrane cause diseases known as laminopathies. Most LMNA mutations cause dilated cardiomyopathy with variable skeletal muscular dystrophy. Cell signaling abnormalities have been discovered in hearts of mouse models of cardiomyopathy caused by LMNA mutations that contribute to pathogenesis. These include abnormally increased signaling by extracellular signal-regulated kinase 1 and kinase 2 and other mitogen-activated protein kinases, protein kinase B/mammalian target of rapamycin complex 1 and transforming growth factor-\u03b2. Preclinical research suggests that specific inhibitors of these abnormally activated cell signaling pathways may be useful in treating human patients with this disease.\n\nID: 29176575\nTitle: Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy.\nAbstract: Endoplasmic reticulum (ER) and lysosomes coordinate a network of key cellular processes including unfolded protein response (UPR) and autophagy in response to stress. How ER stress is signaled to lysosomes remains elusive. Here we find that ER disturbance activates chaperone-mediated autophagy (CMA). ER stressors lead to a PERK-dependent activation and recruitment of MKK4 to lysosomes, activating p38 MAPK at lysosomes. Lysosomal p38 MAPK directly phosphorylates the CMA receptor LAMP2A at T211 and T213, which causes its membrane accumulation and active conformational change, activating CMA. Loss of ER stress-induced CMA activation sensitizes cells to ER stress-induced death. Neurotoxins associated with Parkinson's disease fully engages ER-p38 MAPK-CMA pathway in the mouse brain and uncoupling it results in a greater loss of SNc dopaminergic neurons. This work identifies the coupling of ER and CMA as a critical regulatory axis fundamental for physiological and pathological stress response.\n\nID: 28542436\nTitle: Stress-induced release of Oct-1 from the nuclear envelope is mediated by JNK phosphorylation of lamin B1.\nAbstract: The nuclear lamina can bind and sequester transcription factors (TFs), a function lost if the lamina is abnormal, with missing or mutant lamin proteins. We now show that TF sequestration is not all-or-nothing, but a dynamic physiological response to external signals. We show that the binding of the ubiquitous TF, Oct-1, to lamin B1 was reversed under conditions of cellular stress caused, inter alia, by the chemical methylating agent methylmethanesulfonate (MMS). A search for lamin B1 post-translational modifications that might mediate changes in Oct-1 binding using kinase inhibitors uncovered a role for c-Jun N-terminal kinase (JNK). Phosphoproteomic and site-directed mutagenesis analyses of lamin B1 isolated from control and MMS-treated nuclei identified T575 as a JNK site phosphorylated after stress. A new phospho-T575 specific anti-peptide antibody confirmed increased interphase cellular T575 phosphorylation after cell exposure to certain stress conditions, enabling us to conclude that lamin B1 acts as an interphase kinase target, releasing Oct-1 to execute a protective response to stress.\n\nID: 28423002\nTitle: Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo.\nAbstract: Serum amyloid A (SAA) is an acute phase protein with cytokine-like and chemotactic properties, that is markedly up-regulated during various inflammatory conditions. Several receptors, including FPRL-1, TLR2, TLR4, RAGE, class B scavenger receptors, SR-BI and CD36, have been identified as SAA receptors. This study provides new evidence that SR-BII, splice variant of SR-BI, could function as an SAA receptor mediating its uptake and pro-inflammatory signaling. The uptake of Alexa Fluor488 SAA was markedly (~3 fold) increased in hSR-BII-expressing HeLa cells when compared with mock-transfected cells. The levels of SAA-induced interleukin-8 secretion by hSR-BII-expressing HEK293 cells were also significantly (~3-3.5 fold) higher than those detected in control cells. Moderately enhanced levels of phosphorylation of all three mitogen-activated protein kinases, ERK1/2, and p38 and JNK, were observed in hSR-BII-expressing cells following SAA stimulation when compared with control wild type cells. Transgenic mice with pLiv-11-directed liver/kidney overexpression of hSR-BI or hSR-BII were used to assess the in vivo role of each receptor in SAA-induced pro-inflammatory response in these organs. Six hours after intraperitoneal SAA injection both groups of transgenic mice demonstrated markedly higher (~2-5-fold) expression levels of inflammatory mediators in the liver and kidney compared to wild type mice. Histological examinations of hepatic and renal tissue from SAA-treated mice revealed moderate level of damage in the liver of both transgenic but not in the wild type mice. Activities of plasma transaminases, biomarkers of liver injury, were also moderately higher in hSR-B transgenic mice when compared to wild type mice. Our findings identify hSR-BII as a functional SAA receptor that mediates SAA uptake and contributes to its pro-inflammatory signaling via the MAPKs-mediated signaling pathways.\n\nID: 27827955\nTitle: A Novel Role of Dickkopf-Related Protein 3 in Macropinocytosis in Human Bladder Cancer T24 Cells.\nAbstract: Dickkopf-related protein 3 (Dkk-3) is a potential tumor suppressor reported in various cancer entities. However, we found that Dkk-3 was exceptionally upregulated in bladder cancer T24 cells. To validate the biological role of Dkk-3 other than a tumor suppressor, we examined the function of Dkk-3 in T24 cells. Gene silencing of Dkk-3 inhibited cell growth through inducing G\u2080/G\u2081 cell-cycle arrest. Furthermore, Dkk-3 knock-down caused macropinocytosis accompanied by autophagy, which were canceled in part by their inhibitors 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyladenine (3-MA). The macropinocytosis was induced by the Dkk-3 knock-down when there were sufficient extracellular nutrients. On the other hand, when the nutritional condition was poor, the autophagy was mainly induced by the Dkk-3 knock-down. These data indicated that Dkk-3 has a role in modulating macropinocytotic and autophagic pathways, a distinct function other than a Wnt antagonist.\n\nID: 27591188\nTitle: Nucleoporin-Regulated MAP Kinase Signaling in Immunity to a Necrotrophic Fungal Pathogen.\nAbstract: Pathogen-responsive mitogen-activated protein kinase (MAPK or MPK) cascades relay signals from activated immune receptors across the nuclear envelope to intranuclear targets. However, in plants, little is known about the spatial control of MAPK signaling. Here, we report that the Arabidopsis (Arabidopsis thaliana) nuclear pore complex protein Nup88/MOS7 is essential for immunity to the necrotrophic fungus Botrytis cinerea The mos7-1 mutation, causing a four-amino acid deletion, compromises B. cinerea-induced activation of the key immunoregulatory MAPKs MPK3/MPK6 and reduces MPK3 protein levels posttranscriptionally. Furthermore, MOS7 contributes to retaining a sufficient MPK3 abundance in the nucleus, which is required for full immunity to B. cinerea Finally, we present a structural model of MOS7 and show that the mos7-1 mutation compromises interactions with Nup98a/b, two phenylalanine-glycine repeat nucleoporins implicated in maintaining the selective nuclear pore complex permeability barrier. Together, our analysis uncovered MOS7 and Nup98 as novel components of plant immunity toward a necrotrophic pathogen and provides mechanistic insights into how these nucleoporins coordinate nucleocytoplasmic transport to mount a robust immune response.\n\nID: 27314954\nTitle: Model Predicts That MKP1 and TAB1 Regulate p38\u03b1 Nuclear Pulse and Its Basal Activity through Positive and Negative Feedback Loops in Response to IL-1.\nAbstract: Interleukin-1 mediates inflammation and stress response through nuclear activity of p38\u03b1. Although IL-1 receptor is not degraded, p38\u03b1 activation is transient. IL-1 also causes cell migration and EMT by modulating cell-cell junctions. Although molecules involved in p38 activation are known, mechanism of the transient nuclear response and its basal activity remains unknown. By mathematical modeling of IL1/p38 signaling network, we show that IL-1 induces robust p38\u03b1 activation both in the nucleus and in the cytoplasm/membrane. While nuclear response consists of an acute phase, membrane response resembles a step change. Following stimulation, p38\u03b1 activity returns to a basal level in absence of receptor degradation. While nuclear pulse is controlled by MKP1 through a negative feedback to pp38, its basal activity is controlled by both TAB1 and MKP1 through a positive feedback loop. Our model provides insight into the mechanism of p38\u03b1 activation, reason for its transient nuclear response, and explanation of the basal activity of MKK3/6 and p38\u03b1, which has been experimentally observed by other groups.\n\nID: 27107253\nTitle: Susceptibility of human tonsillar epithelial cells to enterovirus 71 with normal cytokine response.\nAbstract: A recent histopathologic study implicated human tonsillar crypt epithelium as an important site for EV71 replication in EV71-caused fatal cases. This study aimed to confirm the susceptibility of human tonsillar epithelium to EV71. Two human tonsillar epithelial cell lines (UT-SCC-60A and UT-SCC-60B) were susceptive to EV71, and PI3K/AKT, p38, ERK1/2, and JNK1/2 signal pathways were activated. Interferon-\u03b1, IL-8, IL-1\u03b2, IL-6 and IL-12p40 were induced and regulated by PI3K/AKT, p38, ERK1/2, and JNK1/2 signal pathways. PI3K/AKT pathway activation appeared to suppress the induction of TNF-\u03b1, which induced cell survival by inhibiting GSK-3\u03b2. The activation of NF-\u03baB was observed but inhibited by these pathways in EV71 infection. Furthermore, ERK1/2 and JNK1/2 were essential for efficient EV71 replication. Human tonsillar epithelial cells support EV71 replication and display innate antiviral immunity in vitro, indicating that human tonsillar epithelial cells may be novel targets for EV71 infection and replication in vivo.\n\nID: 27002406\nTitle: Glabridin induces apoptosis and autophagy through JNK1/2 pathway in human hepatoma cells.\nAbstract: Extensive research results support the use of herbal medicine or natural food to augment therapy for various cancers. Studies have associated glabridin with numerous biological activities, such as regulating energy metabolism and estrogenic, neuroprotective, antiosteoporotic, and skin-whitening activities. However, how glabridin affects tumor cell autophagy has not been clearly determined. Autophagy is a lysosomal degradation pathway essential for cell survival and tissue homeostasis. In this study, the roles of autophagy and related signaling pathways during glabridin-induced autophagy in human liver cancer cells were investigated. Additionally, the molecular mechanism of the anticancer effects of glabridin in human hepatoma cells was investigated. The results revealed that glabridin significantly inhibited cell proliferation in human hepatoma cells. Glabridin induced apoptosis dose-dependently in Huh7 cells through caspase-3, -8, and -9 activation and PARP cleavage. Furthermore, autophagy was detected as early as 12h after exposure to a low dose of glabridin, as indicated by the up-regulated expression of LC3-II and beclin-1 proteins. The inhibition of JNK1/2 and p38 MAPK by specific inhibitors significantly reduced glabridin-induced activation of caspases-3, -8, and -9. Blocking autophagy sensitize the Huh7 cells to apoptosis. This study demonstrated for the first time that autophagy occurs earlier than apoptosis does during glabridin-induced apoptosis in human liver cancer cell lines. Glabridin induces Huh7 cell death through apoptosis through the p38 MAPK and JNK1/2 pathways and is a potential chemopreventive agent against human hepatoma.\n\nID: 26807190\nTitle: A SILAC-based proteomics elicits the molecular interactome of alisertib (MLN8237) in human erythroleukemia K562 cells.\nAbstract: Alisertib (MLN8237, ALS), an Aurora kinase A (AURKA) inhibitor, exerts potent anti-tumor effects in the treatment of solid tumor and hematologic malignancies in preclinical and clinical studies. However, the fully spectrum of molecular targets of ALS and its anticancer effect in the treatment of chronic myeloid leukemia (CML) are not clear. This study aimed to examine the proteomic responses to ALS treatment and unveil the molecular interactome and possible mechanisms for its anticancer effect in K562 cells using stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data identified that ALS treatment modulated the expression of 1541 protein molecules (570 up; 971 down). The pathway analysis showed that 299 signaling pathways and 459 cellular functional proteins directly responded to ALS treatment in K562 cells. These targeted molecules and signaling pathways were mainly involved in cell growth and proliferation, cell metabolism, and cell survival and death. Subsequently, the effects of ALS on cell cycle distribution, apoptosis, and autophagy were verified. The flow cytometric analysis showed that ALS significantly induced G2/M phase arrest and the Western blotting assays showed that ALS induced apoptosis via mitochondria-dependent pathway and promoted autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways in K562 cells. Collectively, this study provides a clue to quantitatively evaluate the proteomic responses to ALS and assists in globally identifying the potential molecular targets and elucidating the underlying mechanisms of ALS for CML treatment, which may help develop new efficacious and safe therapies for CML treatment.\n\nID: 26762402\nTitle: Obox4-silencing-activated STAT3 and MPF/MAPK signaling accelerate nuclear membrane breakdown in mouse oocytes.\nAbstract: Mouse oocytes begin to mature in vitro once liberated from ovarian follicles. Previously, we showed that oocyte-specific homeobox 4 (Obox4) is critical for maintaining the intact nuclear membrane of the germinal vesicle (GV) in oocytes and for completing meiosis at the metaphase I-II (MI-MII) transition. This study further examines the molecular mechanisms of OBOX4 in regulating GV nuclear membrane breakdown. Maturation-promoting factor (MPF) and MAPK are normally inactive in GV stage oocytes but were activated prematurely in arrested GV stage oocytes by 3-isobutyl-1-metyl-xanthine (IBMX) in vitro after Obox4 RNA interference (RNAi). Furthermore, signal transducer and activator of transcription 3 (STAT3) was significantly activated by Obox4 RNAi. We confirmed that this Obox4 RNAi-induced premature STAT3 and MPF/MAPK activation at the GV stage provoked subsequent GV breakdown (GVBD) despite the opposing force of high cAMP in the IBMX-supplemented medium to maintain intact GV. When cumulus-oocyte complexes were exposed to interferon \u03b1 (IFNA), a STAT3 activator, oocytes matured and cumulus cells expanded to resume nuclear maturation in IBMX-supplemented medium, suggesting that STAT3 activation is sufficient for stimulating the continuation of meiosis. Using Stattic, a specific STAT3 inhibitor, we confirmed that GVBD involves STAT3 activation in Obox4-silenced oocytes. Based on these findings, we concluded that i) Obox4 is an important upstream regulator of MPF/MAPK and STAT3 signaling, and ii) Obox4 is a key regulator of the GV arrest mechanism in oocytes.\n\nID: 26729093\nTitle: Alisertib Induces Cell Cycle Arrest, Apoptosis, Autophagy and Suppresses EMT in HT29 and Caco-2 Cells.\nAbstract: Colorectal cancer (CRC) is one of the most common malignancies worldwide with substantial mortality and morbidity. Alisertib (ALS) is a selective Aurora kinase A (AURKA) inhibitor with unclear effect and molecular interactome on CRC. This study aimed to evaluate the molecular interactome and anticancer effect of ALS and explore the underlying mechanisms in HT29 and Caco-2 cells. ALS markedly arrested cells in G\u2082/M phase in both cell lines, accompanied by remarkable alterations in the expression level of key cell cycle regulators. ALS induced apoptosis in HT29 and Caco-2 cells through mitochondrial and death receptor pathways. ALS also induced autophagy in HT29 and Caco-2 cells, with the suppression of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), but activation of 5' AMP-activated protein kinase (AMPK) signaling pathways. There was a differential modulating effect of ALS on p38 MAPK signaling pathway in both cell lines. Moreover, induction or inhibition of autophagy modulated basal and ALS-induced apoptosis in both cell lines. ALS potently suppressed epithelial to mesenchymal transition (EMT) in HT29 and Caco-2 cells. Collectively, it suggests that induction of cell cycle arrest, promotion of apoptosis and autophagy, and suppression of EMT involving mitochondrial, death receptor, PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways contribute to the cancer cell killing effect of ALS on CRC cells.\n\nID: 26663083\nTitle: Deficiency of Neuronal p38\u03b1 MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.\nAbstract: Amyloid \u03b2 (A\u03b2) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in A\u03b2 generation. Neuroinflammation potentially up-regulates BACE1 expression and increases A\u03b2 production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38\u03b1 MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38\u03b1 MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated A\u03b2 generation in the AD mouse brain. Inhibition of p38\u03b1 MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38\u03b1 MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38\u03b1 MAPK plays a critical role in the regulation of BACE1 degradation and A\u03b2 generation in AD pathogenesis.\n\nID: 26521126\nTitle: Ubiquilin-2 drives NF-\u03baB activity and cytosolic TDP-43 aggregation in neuronal cells.\nAbstract: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo. Here, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor \u03baB (NF-\u03baB) activation in Neuro2A cells. The inhibition of NF-\u03baB stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-\u03baB activation by UBQLN2 species. Live cell imaging and microscopy showed that UBQLN2 aggregates are dynamic structures that promote cytoplasmic accumulation of TAR DNA-binding protein (TDP-43), a major component of ALS inclusion bodies. Furthermore, up-regulation of UBQLN2 species in neurons caused an ER-stress response and increased their vulnerability to death by toxic mediator TNF-\u03b1. Withaferin A, a known NF-\u03baB inhibitor, reduced mortality of Neuro2A cells overexpressing UBQLN2 species. These results suggest that UBQLN2 dysregulation in neurons can drive NF-\u03baB activation and cytosolic TDP-43 aggregation, supporting the concept of pathway convergence in ALS pathogenesis. These Ubiquilin-2 pathogenic pathways might represent suitable therapeutic targets for future ALS treatment.\n\nID: 26241894\nTitle: S-Nitrosylation of Bcl-2 Negatively Affects Autophagy in Lung Epithelial Cells.\nAbstract: Autophagy is a catabolic cellular mechanism involving lysosomal degradation of unwanted cellular components. Interaction between Beclin-1 and Bcl-2 proteins is known to play a critical role in the initiation of autophagy. We report that malignantly transformed lung epithelial cells are resistant to autophagy and express lower basal levels of autophagic proteins, Beclin-1 and LC3-II as compared to non-tumorigenic cells. Additionally, increased levels of nitric oxide (NO) and Bcl-2 were observed in transformed cells. Nitric oxide was found to negatively regulate autophagy initiation and autophagic flux by nitrosylating Bcl-2 and stabilizing its interaction with Beclin-1, resulting in inhibition of Beclin-1 activity. An increase in the apoptotic initiator caspase-9 and the apoptosis and autophagy-associated kinase p38/MAPK in both cell types indicated possible autophagy-apoptosis crosstalk. Pre-treatments with ABT-737 (Bcl-2 inhibitor) and aminoguanidine (NO inhibitor), and transfection with a non-nitrosylable Bcl-2 cysteine double-mutant plasmid resulted in increased autophagic flux (LC3-II/p62 upregulation) corresponding with decreased S-nitrocysteine expression, thus corroborating the regulatory role of Bcl-2 S-nitrosylation in autophagy. In conclusion, our study reveals a novel mechanism of autophagy resistance via post-translational modification of Bcl-2 protein by NO, which may be critical in driving cellular tumorigenesis.\n\nID: 25926528\nTitle: The effects of red ginseng saponin fraction-A (RGSF-A) on phagocytosis and intracellular signaling in Brucella abortus infected RAW 264.7 cells.\nAbstract: This study indicated that RGSF-A caused a marked reduction in the adherence, internalization and intracellular growth of Brucella abortus in RGSF-A-treated cells. Furthermore, a decline in the intensity of F-actin fluorescence was observed in RGSF-A-treated cells compared with untreated B. abortus-infected cells. In addition, an evaluation of phagocytic signaling proteins by Western blot analysis revealed an apparent reduction of ERK and p38\u03b1 phosphorylation levels in B. abortus-infected RGSF-A-treated cells compared with the control. Upon intracellular trafficking of the pathogen, a higher number of B. abortus-containing phagosomes colocalized with LAMP-1 in RGSF-A-treated cells compared with control cells. These results strongly suggest that inhibition of B. abortus uptake could be mediated by suppression in the activation of MAPKs signaling proteins phospho-ERK 1/2, and p38 levels. On the other hand, inhibition of intracellular replication results from the enhancement of phagolysosome fusion in host macrophages. This study highlights the phagocytic and intracellular modulating effect of RGSF-A and its potential as an alternative remedy to control B. abortus infection.\n\nID: 25792811\nTitle: Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway.\nAbstract: Osteosarcoma (OS) is the most common malignant bone tumor occurring mostly in children and adolescents between 10 and 20 years of age with poor response to current therapeutics. Alisertib (ALS, MLN8237) is a selective Aurora kinase A inhibitor that displays anticancer effects on several types of cancer. However, the role of ALS in the treatment of OS remains unknown. This study aimed to investigate the effects of ALS on the cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK) signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS) generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2) in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy.\n\nID: 25790465\nTitle: Nuclear envelope protein Lem2 is required for mouse development and regulates MAP and AKT kinases.\nAbstract: The nuclear lamina, along with associated nuclear membrane proteins, is a nexus for regulating signaling in the nucleus. Numerous human diseases arise from mutations in lamina proteins, and experimental models for these disorders have revealed aberrant regulation of various signaling pathways. Previously, we reported that the inner nuclear membrane protein Lem2, which is expressed at high levels in muscle, promotes the differentiation of cultured myoblasts by attenuating ERK signaling. Here, we have analyzed mice harboring a disrupted allele for the Lem2 gene (Lemd2). No gross phenotypic defects were seen in heterozygotes, although muscle regeneration induced by cardiotoxin was delayed. By contrast, homozygous Lemd2 knockout mice died by E11.5. Although many normal morphogenetic hallmarks were observed in E10.5 knockout embryos, most tissues were substantially reduced in size. This was accompanied by activation of multiple MAP kinases (ERK1/2, JNK, p38) and AKT. Knockdown of Lem2 expression in C2C12 myoblasts also led to activation of MAP kinases and AKT. These findings indicate that Lemd2 plays an essential role in mouse embryonic development and that it is involved in regulating several signaling pathways. Since increased MAP kinase and AKT/mTORC signaling is found in other animal models for diseases linked to nuclear lamina proteins, LEMD2 should be considered to be another candidate gene for human disease.\n\nID: 25632225\nTitle: Alisertib induces cell cycle arrest and autophagy and suppresses epithelial-to-mesenchymal transition involving PI3K/Akt/mTOR and sirtuin 1-mediated signaling pathways in human pancreatic cancer cells.\nAbstract: Pancreatic cancer is the most aggressive cancer worldwide with poor response to current therapeutics. Alisertib (ALS), a potent and selective Aurora kinase A inhibitor, exhibits potent anticancer effects in preclinical and clinical studies; however, the effect and underlying mechanism of ALS in the pancreatic cancer treatment remain elusive. This study aimed to examine the effects of ALS on cell growth, autophagy, and epithelial-to-mesenchymal transition (EMT) and to delineate the possible molecular mechanisms in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that ALS exerted potent cell growth inhibitory, pro-autophagic, and EMT-suppressing effects in PANC-1 and BxPC-3 cells. ALS remarkably arrested PANC-1 and BxPC-3 cells in G2/M phase via regulating the expression of cyclin-dependent kinases 1 and 2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. ALS concentration-dependently induced autophagy in PANC-1 and BxPC-3 cells, which may be attributed to the inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase (p38 MAPK), and extracellular signal-regulated kinases 1 and 2 (Erk1/2) but activation of 5'-AMP-dependent kinase signaling pathways. ALS significantly inhibited EMT in PANC-1 and BxPC-3 cells with an increase in the expression of E-cadherin and a decrease in N-cadherin. In addition, ALS suppressed the expression of sirtuin 1 (Sirt1) and pre-B cell colony-enhancing factor/visfatin in both cell lines with a rise in the level of acetylated p53. These findings show that ALS induces cell cycle arrest and promotes autophagic cell death but inhibits EMT in pancreatic cancer cells with the involvement of PI3K/Akt/mTOR, p38 MAPK, Erk1/2, and Sirt1-mediated signaling pathways. Taken together, ALS may represent a promising anticancer drug for pancreatic cancer treatment. More studies are warranted to investigate other molecular targets and mechanisms and verify the efficacy and safety of ALS in the treatment of pancreatic cancer.\n\nID: 42496868\nTitle: Erratum to: Superenhancers activate the autophagy-related genes Beclin1 and LC3B to drive metastasis and drug resistance in osteosarcoma.\nAbstract: \n\nID: 42496832\nTitle: The miR-335-5p/DKK1/autophagy axis regulates TNF-\u03b1-mediated dysfunction of dental pulp stem cells.\nAbstract: Dental pulp stem cells (DPSCs) play a critical role in maintaining dental pulp homeostasis and supporting dentin-pulp complex regeneration, while tumor necrosis factor-\u03b1 (TNF-\u03b1)-mediated inflammation severely impairs their biological functions. This study explored the role of the miR-335-5p/DKK1/autophagy axis in TNF-\u03b1-induced DPSCs dysfunction. Human DPSCs were stimulated with 20\u00a0ng/mL TNF-\u03b1; miR-335-5p overexpression and DKK1 silencing were achieved via transfection. qRT-PCR, Western blot, SA-\u03b2-gal staining, immunofluorescence, transmission electron microscopy, ALP/ARS staining, and dual-luciferase assay were used to detect related indicators. Results showed TNF-\u03b1 downregulated miR-335-5p, upregulated DKK1, inhibited autophagy, induced senescence, disrupted cytoskeleton, and suppressed osteogenesis; miR-335-5p directly targeted DKK1's 3'-UTR. Overexpressing miR-335-5p or silencing DKK1 restored DPSCs' autophagic flux, alleviated senescence, and rescued osteogenic potential. In conclusion, the miR-335-5p/DKK1/autophagy axis mediates TNF-\u03b1-induced DPSCs dysfunction, and targeting this axis may improve stem cell-based dental pulp and bone reconstruction under inflammation.\n\nID: 42496831\nTitle: Circulating factors induced by time-restricted eating drive metabolic reprogramming in endothelial cells.\nAbstract: Age-related endothelial dysfunction in the cerebral microcirculation contributes significantly to the pathogenesis of vascular cognitive impairment and dementia (VCID). Time-restricted eating (TRE) has emerged as a promising lifestyle intervention with beneficial effects on metabolic and vascular health; however, the mechanisms by which TRE influences the brain microvasculature remain incompletely understood. In particular, the role of circulating factors induced by TRE in modulating endothelial function has not been systematically investigated. Here, we tested the hypothesis that circulating factors derived from humans practicing time-restricted eating (TRE) induce protective and adaptive responses in human cerebromicrovascular endothelial cells. Using a serum transfer bioassay, endothelial cells were treated with serum obtained from aged individuals with or without TRE, followed by transcriptomic profiling. We demonstrate that TRE-associated serum elicits a robust and coordinated transcriptional reprogramming in human cerebromicrovascular endothelial cells, characterized by activation of stress-responsive and metabolic pathways and suppression of anabolic programs. Gene set enrichment analysis revealed significant activation of the integrated stress response (ISR)/ATF4 axis and suppression of mTORC1 signaling, consistent with a shift toward a catabolic, stress-adaptive state. These changes were accompanied by marked induction of the stress-responsive cytokine GDF15. At the mitochondrial level, TRE serum promoted increased expression of mitochondrial DNA-encoded oxidative phosphorylation components without activation of canonical mitochondrial biogenesis pathways, suggesting functional remodeling. Upstream regulator analysis identified coordinated activation of stress- and metabolism-associated transcription factors, including ATF4, FOXO, and KLF family members, alongside inhibition of anabolic regulators such as SREBF1/2. Notably, canonical endothelial functional programs, including autophagy and blood-brain barrier maintenance, were not coordinately activated. While individual angiogenesis-related genes were modestly upregulated, these changes did not translate into a coordinated pathway-level response. Collectively, these findings demonstrate that circulating factors induced by TRE promote a distinct endothelial phenotype characterized by metabolic reprogramming and stress adaptation rather than classical inflammatory or reparative responses. This work provides new mechanistic insight into how lifestyle interventions may influence cerebrovascular aging and identifies circulating factors as key mediators linking systemic metabolic state to endothelial function.\n\nID: 42496777\nTitle: A combination of artemisinin, moxidectin, and doxorubicin drugs can selectively and efficiently induce apoptosis in acute lymphoblastic and chronic myeloid leukemia cells in vitro and ex vivo.\nAbstract: Acute lymphoblastic (ALL) and chronic myeloid (CML) leukemias are blood cancers that often resist traditional chemotherapy and other treatments. This is likely due to their ability to evade apoptosis. Therefore, inducing apoptosis in leukemia cells using innovative drug combinations may be the most effective therapeutic approach. Methods for multidrug combinations involving three or more drugs are scarce and much more complex to analyze. To address this issue, we propose an effective concentration 50 (EC50)-based, three-step method. The first step determines the lowest EC50 for each drug (e.g., artemisinin, chloroquine, primaquine, mefloquine, ivermectin, moxidectin, doxorubicin, and minocycline) by analyzing four cell endpoints (e.g., cell cycle, sub-G1, mitochondrial membrane potential (\u0394\u03a8m), autophagy (lysosomes), and cleaved caspase 3 (CC3)) on K562 cells. Step two involves establishing the deleterious effect of the EC50-based drug combination at concentrations of single drugs at 1-, \u00bd-, and \u00bc-EC50, respectively, on K562 leukemia cells. Step three involves using the optimal combined drugs to evaluate the same cellular endpoints in other non-leukemic and leukemic cells. We found that the combination of AM (1 \u00b5M), MD (10 \u00b5M), and DR (1.5 \u00b5M), i.e., at \u00bd EC50, induced cell cycle arrest in the S (25% \u00b1 13, N\u2009=\u20094) and G2/M (55% \u00b1 18, N\u2009=\u20094) phases, a drastic loss of \u0394\u03a8m (81% \u00b1 6, N\u2009=\u20094), high lysosome accumulation (82% \u00b1 10, N\u2009=\u20094), and CC3 (83% \u00b1 13, N\u2009=\u20094), as evidence of apoptosis in K562 and Jurkat cells and ex vivo ALL and CML cells. The combined drugs were innocuous to peripheral blood lymphocytes (PBLs) (S phase\u2009=\u200940%; G2/M\u2009=\u200926%; \u0394\u03a8m\u2009=\u20094%; lysosomes\u2009=\u20093%; CC3\u2009=\u20094%; n\u2009=\u20093). Our approach to combining drugs has the potential to provide a new pharmacological treatment for leukemias.\n\nID: 42496506\nTitle: An Autopsy Report of Beta-Propeller Protein-Associated Neurodegeneration with 68-Year Survival, Focusing on Isoform-Specific Distribution of Hyperphosphorylated Tau.\nAbstract: Background and Clinical Significance: Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation caused by pathogenic variants in WDR45. Although its clinical course and neuroimaging features are increasingly recognized, detailed neuropathological characterization, especially at its terminal stage, remains limited. Case presentation: We report a 68-year-old woman with a heterozygous WDR45 splice-site variant (NM_007075.4:c.830+1G>A), representing the longest-surviving case of SENDA/BPAN described to date. After static developmental delay in childhood, she rapidly developed progressive parkinsonism, dystonia, and cognitive decline in early adulthood, ultimately becoming bedridden with profound motor and autonomic dysfunction. Serial MRI demonstrated progressive cerebral and cerebellar atrophy with iron-related signal changes in the globus pallidus and substantia nigra. She died of sepsis at the age of 68 and was subjected to an autopsy including the brain. Neuropathological findings: Autopsy revealed severe, diffuse neuronal loss and gliosis throughout the central nervous system, with marked iron deposition and complete neuronal loss in the globus pallidus and substantia nigra. Immunohistochemistry demonstrated widespread tau pathology. Notably, neuronal tau inclusions contained both four-repeat (4R) and three-repeat (3R) isoforms, whereas glial tau was predominantly 4R-positive, indicating a mixed neuronal 4R/3R and glial 4R-dominant tauopathy. Perivascular and subpial 4R-tau-dominant deposits consistent with aging-related tau astrogliopathy were also present. LC3-positive and ferritin-positive cells suggested impaired autophagic flux, supporting the proposed autophagy-related pathogenesis of SENDA/BPAN. Conclusions: This case provides comprehensive clinicopathological insight into end-stage SENDA/BPAN, highlighting distinctive tau isoform patterns in neurons versus glia and pathological evidence of autophagy dysfunction. These findings expand the neuropathological spectrum of SENDA/BPAN and may inform future mechanistic and therapeutic research.\n\nID: 42496187\nTitle: Lysosomes and Supersulfides: Emerging Links in Cellular Metabolism and Homeostasis.\nAbstract: Supersulfides, a class of catenated sulfur-containing biomolecules, are increasingly recognized as key regulators of redox signaling, mitochondrial function, and inflammatory responses. Recent evidence suggests that lysosomes, central organelles for intracellular degradation and nutrient sensing, are closely linked to supersulfide metabolism through lysosomal acidification, cysteine metabolism, and autophagy. Conversely, supersulfides modulate lysosomal activity and inflammatory responses. This review summarizes recent progress in supersulfide biology and lysosomal regulation and discusses evidence supporting functional interactions between these systems. We propose the lysosome-supersulfide axis as a new concept in cellular homeostasis and metabolic regulation.\n\nID: 42495964\nTitle: Targeting NAE1 suppresses osteoclastogenesis via dual regulation of ferritinophagy and ACSL3-mediated ferroptosis.\nAbstract: Neddylation regulates diverse cellular processes, yet its role in osteoclast-mediated bone resorption is poorly understood. Here, we identify NAE1 (NEDD8 activating enzyme E1 subunit 1)-mediated neddylation as a critical regulator of postmenopausal osteoporosis and osteoclast differentiation through two distinct regulatory mechanisms. Pharmacological inhibition of Nae1 or myeloid-specific genetic ablation of Nae1 attenuated osteoclastogenesis in vitro and ameliorated ovariectomy (OVX)-induced osteoporosis in vivo without impairing osteoblast function. Mechanistically, Nae1 depletion disrupted intracellular iron metabolism, thereby suppressing ferritinophagy initiation in osteoclast precursors. Concurrently, integrated transcriptomics and affinity purification-mass spectrometry revealed ACSL3 as a direct neddylation substrate. Nae1-mediated neddylation modulates monounsaturated fatty acid (MUFA) biosynthesis, regulating the sensitivity of bone marrow-derived macrophages (BMDMs) to ferroptosis. This dual regulatory mechanism coordinately governs ferritinophagy initiation in iron metabolism and the sensitivity to ferroptosis mediated by ACSL3 neddylation, thereby critically influencing osteoclastogenesis. Clinically, serum MUFA levels positively correlated with bone mineral density (r\u2009=\u20090.329, p\u2009<\u20090.05). These findings support MLN4924, a clinical-stage NAE inhibitor, as a potential therapeutic strategy for osteoporosis and define an Nae1-ACSL3-MUFA-ferroptosis axis regulating osteoclast metabolism.Abbreviations: 4-HNE: 4-hydroxynonenal; ACP5/TRAP: acid phosphatase, tartrate resistant; ACSL3: acyl-CoA synthetase long chain family member 3; ACSL4: acyl-CoA synthetase long chain family member 4; BGLAP/OCN: bone gamma-carboxyglutamate protein; BMD: bone mineral density; BMDMs: bone marrow-derived macrophages; BV/TV: bone volume per total volume; CHX: cycloheximide; cKO: conditional knockout; co-IP: co-immunoprecipitation; CTSK: cathepsin K; DFO: deferoxamine; MDS: myelodysplastic syndrome; MUFA: monounsaturated fatty acid; NAE1: NEDD8 activating enzyme E1 subunit 1; NCOA4: nuclear receptor coactivator 4; NEDD8: NEDD8 ubiquitin like modifier; NFE2L2: NFE2 like bZIP transcription factor 2; NFATC1: nuclear factor of activated T cells 1; OC: osteoclast; OVX: ovariectomy; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; RUNX2: RUNX family transcription factor 2; SLC40A1: solute carrier family 40 member 1; SLC7A11: solute carrier family 7 member 11; Tb.N: trabecular number; Tb.Sp: trabecular separation; Tb.Th: trabecular thickness; TFRC: transferrin receptor; TNFSF11/RANKL: TNF superfamily member 11; UBE2M: ubiquitin conjugating enzyme E2 M.\n\nID: 42495963\nTitle: Cytostatic autophagy: an underappreciated form of autophagy and its ramifications in cancer.\nAbstract: Macroautophagy/autophagy is a well-established homeostatic mechanism that contributes to the integrity of multiple regulatory biological activities including but not limited to the gastro-intestinal tract and cognitive integrity. Autophagy also plays a central role in tissue regeneration, metamorphosis and development whereas defects in autophagy are associated with a wide range of disorders including metabolic diseases such as diabetes, organ pathophysiologies including liver, lung and heart disease, cancer, and microbial infection. In the field of cancer therapy, most research efforts have focused on cytoprotective autophagy, with substantial preclinical and clinical studies designed to interrogate the outcomes of pharmacologically (or genetically in preclinical work) inhibiting autophagy to enhance the efficacy of chemotherapeutic agents. There is lesser but nevertheless robust evidence for the cytotoxic function of autophagy while our laboratory and a few others have identified the nonprotective form of this cellular response. However, cytostatic autophagy, a distinct functional outcome of autophagy characterized by sustained proliferative arrest, has remained relatively underexplored. Cytostatic autophagy can be defined as a cellular condition in which autophagy activation coincides with durable proliferative arrest, and in which genetic or pharmacological inhibition of autophagy relieves the growth-arrest phenotype without inducing overt cytotoxicity. In this review, we provide the first comprehensive synthesis of the scientific literature addressing cytostatic autophagy, tracing its historical development and consolidating the experimental evidence that led to its current conceptual definition. We further discuss the molecular mechanisms underlying cytostatic autophagy, including the selective degradation of key cell-cycle regulators and the interplay between autophagy and senescence-associated signaling pathways.\n\nID: 42495958\nTitle: Nucleophagy as an emerging therapeutic vulnerability in cancer.\nAbstract: Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in homologous recombination-deficient (HRD) cancers by trapping PARP1 on DNA, causing replication fork collapse, DNA double-strand breaks, and ultimately cell death. However, primary and acquired resistance to PARPi remains a major clinical challenge. Here, we describe a previously unrecognized mechanism for the resolution of cytotoxic trapped PARP1 through TEX264-mediated nucleophagy. We identify the p97-TEX264-nucleophagy axis as a critical pathway for the clearance of trapped PARP1 and a promising therapeutic target for overcoming PARPi resistance in HRD cancers.\n\nID: 42495818\nTitle: CROP2, a Retriever-PROPPIN complex mediating protein export from endosomes to the plasma membrane in human cells.\nAbstract: Endosomes generate tubulo-vesicular carriers to redistribute proteins between plasma membrane, Golgi, and lysosomes. These transport routes employ distinct combinations of sorting nexins with complexes such as Retromer or Retriever. We now show that, while Retromer associates with the PROPPIN WIPI1 to form the previously described CROP complex, Retriever associates with WIPI2, forming CROP2. WIPI2 integrates into Retriever-dependent coat complexes since it interacts both with the Commander subunit CCDC93 and its cognate sorting nexin SNX17. CROP and CROP2 are exclusive in their physical associations and pathway selective. Whereas CROP2 is required for endosomal exit of Integrin \u03b21, it does not affect CROP-dependent cargos such as EGFR or GLUT1. Vice versa, CROP is not required for Integrin \u03b21 trafficking. WIPI1 and WIPI2 rely on similar molecular features. Their activity depends on the same FSSS motif to integrate into Retromer and Retriever complexes, respectively, and on an amphipathic membrane-inserting \u03b1-helix, which conveys membrane fission activity to PROPPINs. This suggests that Retromer and Retriever coats integrate distinct PROPPIN isoforms to promote fission of the respective endosomal carriers formed by them.\n\nID: 42495773\nTitle: Evaluation of Punicalagin as a multi\u2011targeted therapeutic agent against endometrial cancer.\nAbstract: Endometrial cancer (EC) has become an increasing clinical concern as the incidence is rising, and treatment options available for advanced disease or recurrent disease are limited. In the present study, the anticancer potential of punicalagin (PCG), a natural ellagitannin polyphenol that comes from pomegranate, was characterized using both in vitro and in vivo models in EC. Two EC cell lines (Ishikawa and SNU\u2011539) treated with increasing doses of PCG showed dose\u2011dependent inhibition of cell proliferation and demonstrated a decrease in colony formation. PCG inhibited Transwell migration and an increase in E\u2011cadherin expression, indicating an inhibition of epithelial\u2011mesenchymal transition. Further experimental work characterized the mechanisms by which PCG acted and revealed that it decreased the mitochondrial membrane potential and subsequently increased levels of reactive oxygen species, which led to apoptosis as shown by increased BAX expression and Hoechst/PI staining. In addition, PCG showed signs of autophagy, especially in the Ishikawa cells, as indicated by increased levels of LC3\u2011IIB and the formation of autophagic vacuoles. In vivo studies using a xenograft mouse model showed that treatment with PCG significantly reduced tumor volume and weight, whereas body weight was not significantly affected, thus highlighting strong anticancer efficacy coupled with very low toxicity. Overall, the present study highlights PCG as a promising natural compound with multitarget anticancer activity against EC and warrants further preclinical and clinical research as a potential treatment option.\n\nID: 42495771\nTitle: circRNA_013145\u2011miR\u2011185\u20115p\u2011RhoA axis: A novel mechanism in the pathophysiology of diabetes\u2011induced erectile dysfunction.\nAbstract: Diabetes mellitus\u2011induced erectile dysfunction (DMED) is a common diabetic complication characterized by endothelial dysfunction and corpus cavernosum (CC) remodeling. Although circular RNAs (circRNAs) have been implicated in diabetic vascular diseases, their roles in DMED remain largely unknown. The present study investigated the biological function and underlying mechanism of circRNA_013145 in DMED. CircRNA microarray analysis identified circRNA_013145 as a significantly upregulated circRNA in penile tissue from DMED rats. Its biological function was evaluated using loss\u2011of\u2011function and rescue experiments in high glucose (HG)\u2011treated CC smooth muscle cells (CCSMCs), human umbilical vein endothelial cells (HUVECs) and a DMED rat model. circRNA_013145 expression was markedly increased in DMED penile tissue and HG\u2011treated cells. circRNA_013145 knockdown attenuated HG\u2011induced oxidative stress, inflammation, apoptosis, autophagy and phenotypic transformation, while improving endothelial function and cell viability. Mechanistically, circRNA_013145 served as a molecular sponge for miR\u2011185\u20115p, thereby positively regulating RhoA expression. Rescue experiments demonstrated that inhibition of miR\u2011185\u20115p partially abolished the protective effects of circRNA_013145 knockdown. Furthermore, adenovirus\u2011mediated knockdown of circRNA_013145 significantly improved erectile function and alleviated cavernosal pathological injury in DMED rats, as evidenced by an increased intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio, enhanced CD31 expression and reduced collagen deposition. In conclusion, circRNA_013145 promotes the progression of DMED through the miR\u2011185\u20115p/RhoA axis. Targeting circRNA_013145 may represent a potential therapeutic strategy for DMED.\n\nID: 42495756\nTitle: TPD54 contributes to docetaxel resistance through modulation of P\u2011glycoprotein localization and activity in oral squamous cell carcinoma cells.\nAbstract: Tumor protein D52 (TPD52) family proteins are involved in the proliferation, survival and malignant progression of oral squamous cell carcinoma (OSCC). However, their roles in chemoresistance remain incompletely understood. The present study investigated the contribution of TPD52 family proteins to anticancer drug resistance, with particular emphasis on tumor protein D54 (TPD54). OSCC cells were treated with cisplatin, 5\u2011fluorouracil, or docetaxel (DTX), and the expression of TPD52 family members was examined. Gain\u2011 and loss\u2011of\u2011function analyses were performed to evaluate cell viability, apoptotic responses, cytochrome p450 (P450) and P\u2011glycoprotein (P\u2011gp) activities, protein expression, intracellular localization and membrane/cytosol distribution. Anticancer drug treatment increased the expression of TPD52, TPD53 and TPD54. Among these family members, TPD54 showed the strongest association with DTX resistance by attenuating the reduction in cell viability without affecting cell\u2011cycle progression. TPD54 overexpression attenuated DTX\u2011associated apoptotic responses and was associated with changes in apoptosis\u2011, ferroptosis\u2011, and autophagy\u2011related marker proteins. TPD54 expression had little effect on the activities of P450 3A4 or P450 1B1 but significantly increased P\u2011gp activity. Membrane/cytosol fractionation demonstrated increased membrane localization of endogenous P\u2011gp following TPD54 overexpression, whereas co\u2011immunoprecipitation and immunocytofluorescence analyses revealed an association and partial co\u2011localization between TPD54 and P\u2011gp. These findings suggest that TPD54 contributes to DTX resistance in OSCC cells through modulation of P\u2011gp localization and activity. The present study identifies TPD54 as a potential contributor to P\u2011gp\u2011associated chemoresistance and provides a basis for further investigation of the molecular mechanisms underlying multidrug resistance in OSCC.\n\nID: 42495706\nTitle: NUPR1 in breast cancer: mechanisms and potential applications.\nAbstract: Breast cancer continues to present formidable clinical challenges, particularly in triple-negative and endocrine-resistant subtypes where adaptive stress mechanisms drive therapeutic failure. Nuclear protein 1 (NUPR1), an intrinsically disordered protein, has emerged as a non-mutational hub that has been implicated in integrating metabolic, transcriptional, and cell-survival signals associated with malignant progression. This Review examines how NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress. We discuss its causal roles in endocrine and chemoresistance through chromatin-associated cooperation with estrogen receptor \u03b1, activation of DNA-damage repair, and cell-cycle checkpoint control, as well as its contributions to metastatic dissemination via extracellular vesicle-mediated niche remodeling and immunosuppressive macrophage polarization. Furthermore, we evaluate emerging therapeutic avenues, from small-molecule inhibitors and single-domain antibody degraders that disrupt NUPR1 nuclear trafficking, to metabolic drug repurposing strategies such as statins that intercept the insulin-NUPR1 axis. Elucidating NUPR1 biology represents a paradigm shift toward targeting dynamic, stress-adaptive dependencies in breast cancer, offering new precision-oncology opportunities.\n\nID: 42495647\nTitle: Decoding early lung adenocarcinoma progression by single-cell and spatial transcriptomics reveals a CMA-related prognostic signature.\nAbstract: Lung adenocarcinoma (LUAD) progression from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) is accompanied by molecular heterogeneity and tumor microenvironment remodeling. Chaperone-mediated autophagy (CMA) regulates tumor cell homeostasis, metabolic adaptation, and stress responses, but its dynamic alterations and prognostic significance during the AIS/MIA-to-IAC progression of LUAD remain unclear. We integrated the single-cell transcriptomic dataset GSE189357 and the spatial transcriptomic dataset GSE189487 with bulk transcriptomic data from TCGA-LUAD, GTEx, and the GEO validation cohorts GSE31210 and GSE50081 to characterize CMA-related features during the AIS/MIA-to-IAC progression of LUAD. CMA activity and myeloid remodeling were analyzed at the single-cell and spatial levels. Candidate genes were identified by combining tumor-normal differential expression analysis in TCGA-LUAD with weighted gene co-expression network analysis. Multiple machine learning algorithms were compared to construct and externally validate a prognostic model. Biological and clinical relevance was further assessed through clinicopathological, pathway, immune, cell-cell communication, drug sensitivity, and in vitro analyses. CMA-related activity showed marked cell-type specificity and spatial heterogeneity during the AIS/MIA-to-IAC progression of LUAD, with the most prominent changes in the myeloid compartment. Myeloid re-clustering revealed enrichment of cDC2 and APOE+ lipid-associated TAMs in IAC, whereas FABP4+ metabolic TAMs and immature neutrophils decreased. By integrating tumor-normal differential expression analysis with weighted gene co-expression network analysis, 122 candidate genes were identified, and a 15-gene CMA-related prognostic signature was established using a random survival forest model. This signature showed robust prognostic stratification in TCGA-LUAD, GSE31210, and GSE50081. The high-risk group had poorer survival, more advanced stage, and enrichment of malignant pathways including GLYCOLYSIS, G2M CHECKPOINT, MTORC1 SIGNALING, E2F TARGETS, and MYC TARGETS. The low-risk group showed higher stromal and immune scores and stronger immune activity. THBS1 signaling was restricted to high-risk epithelial communication, with fibroblasts as the major signal senders. In vitro experiments showed that MGP overexpression inhibited lung cancer cell proliferation, colony formation, migration, and invasion. This study characterized CMA-related heterogeneity during LUAD progression from AIS to IAC and established a robust 15-gene prognostic signature. Fibroblast-derived THBS1 signaling and MGP may contribute to the high-risk phenotype and provide insight into early LUAD evolution and risk stratification.\n\nID: 42495642\nTitle: Targeted lipid metabolism screening uncovers regulatory effects on the STING immune response in mevalonate, eicosanoid and fatty acid pathways.\nAbstract: The cGAS/STING pathway is a critical signaling hub that orchestrates type I interferon (IFN) responses, autophagy, and programmed cell death in response to double-stranded DNA (dsDNA) or cyclic dinucleotides. While traditionally characterized as a sensor of foreign or mis-localized self dsDNA, recent evidence demonstrates that STING also integrates information about the homeostasis of cellular lipid biosynthesis into the innate inflammatory response. This integration occurs most notably through STING's sensitivity to de novo cholesterol synthesis. However, given that mammalian cells undergo widespread lipid metabolic reprogramming, characterized by alterations in the synthesis of many lipid species in addition to cholesterol, during processes such as malignant transformation to cancer or during infection by intracellular pathogens, we hypothesized that STING function may be regulated by perturbations in other undescribed lipid pathways. To investigate potential other facets of the STING-lipid interface, we have performed a targeted small molecule screen across multiple lipid metabolic pathways, including the mevalonate, PPAR (fatty acid), and arachidonic acid pathways. Our findings reveal that positively and negatively perturbing enzymes within these diverse lipid paths including lipoxygenases and cyclooxygenases can significantly modulate STING-dependent signal transduction and transcriptional programs, identifying metabolic nodes that link lipid homeostasis with innate immune signaling. These results suggest that existing lipid-lowering and metabolic therapies may have unappreciated immunomodulatory effects on STING applicable in cancer and infectious disease, offering new opportunities for therapeutic intervention.\n\nID: 42495282\nTitle: GSH-Responsive Co-Delivery of Chrysin and 3\u2011Methyladenine Disrupts Tumor Adaptive Stress for Synergistic Antitumor Therapy.\nAbstract: Cancer remains a major global health challenge, and conventional therapies are still limited by poor tumor specificity, therapeutic resistance, and systemic side effects. Herein, we developed a glutathione (GSH)-responsive FFSSFF coacervate system for the codelivery of chrysin (CH) and the autophagy inhibitor 3-methyladenine (3-MA) to induce tumor-selective autophagic stress. CH activated endoplasmic reticulum stress and promoted autophagy through the GRP78/PERK and Akt/mTOR signaling pathways, while 3-MA simultaneously disrupted autophagic flux, leading to intracellular homeostasis imbalance, mitochondrial dysfunction, excessive reactive oxygen species accumulation, and tumor cell death. The resulting CH/3-MA@FFSSFF coacervates exhibited favorable physicochemical properties, GSH-responsive behavior, efficient intracellular uptake, and selective accumulation in tumor cells. Both in vitro and in vivo experiments demonstrated potent antitumor activity of the CH/3-MA@FFSSFF system. In particular, in an orthotopic lung cancer model, CH/3-MA@FFSSFF effectively suppressed tumor growth, prolonged median survival time, and inhibited tumor cell migration and invasion. Collectively, this study presents a promising liquid-liquid phase separation-derived coacervate platform for targeted combinational cancer therapy through the induction of autophagic stress, with enhanced therapeutic efficacy and reduced off-target toxicity.\n\nID: 42494850\nTitle: Host protein cleavage by Dengue and Zika virus NS3 proteases: from substrate identification to potential biological consequences.\nAbstract: Dengue virus (DENV) and Zika virus (ZIKV) are medically important orthoflaviviruses that utilize the multifunctional NS3 protease, in complex with its cofactor NS2B, for viral replication and host modulation. Here, we summarize current knowledge of host proteins targeted by NS3 proteases and discuss recent advances in proteomic and computational approaches for identifying these substrates. We further discuss evidence showing that NS2B3-mediated cleavage alters innate immune signaling, autophagy, protein translation, and cytoskeletal dynamics. In addition, we compare the host substrate specificities of DENV and ZIKV proteases, emphasizing both shared mechanisms and virus-specific differences that may contribute to their distinct disease manifestations. A deeper understanding of NS3-mediated host protein cleavage will provide critical insights into orthoflavivirus biology and further establish NS3 as a promising target for antiviral intervention.\n\nID: 42494769\nTitle: Editorial: Ramadan intermittent fasting model as a catalyst for healthy aging and disease mitigation.\nAbstract: \n\nID: 42494762\nTitle: Probiotic co-administration attenuates developmental cafeteria diet-induced cellular stress and NLRP3 inflammasome signaling in the spleen.\nAbstract: Early life exposure to obesogenic diets is increasingly associated with persistent immunometabolic dysregulation. However, the effects of such dietary stress on splenic apoptosis, autophagy, and inflammasome signaling during the developmental period remain insufficiently characterized. This study investigated whether probiotic supplementation modulates cafeteria diet (Cd)-induced molecular alterations in splenic tissue during the post-weaning period. Twenty-one-day-old male Wistar rats were randomly assigned to four groups (n = 7/group): Control (Cnt), Cafeteria diet (Cd), SCD Probiotics (Prb), and Cafeteria diet plus probiotic (Cd+Prb). Interventions were maintained from postnatal day 21 to 56. Splenic apoptosis, autophagy, and inflammasome related markers were evaluated using RT-qPCR and immunohistochemistry. Cafeteria diet exposure shifted the spleen toward a pro-apoptotic state, characterized by a relative decrease in BCL2 fold-change pattern and relative increases in BAK and Caspase-3 fold-change patterns, while protein analysis confirmed marked elevations in Caspase-3 and BAX (both p < 0.0001). Autophagy-related alterations included reduced ATG5 expression and marked p62 accumulation, consistent with impaired autophagic regulation, with corresponding protein-level differences for ATG5 and p62 (both p < 0.0001). Inflammasome-associated signaling was reflected by relative increases in NLRP3 and IL-18 fold-change patterns together with higher protein-level immunoreactivity, with strong protein-level significance (p < 0.0001). Probiotic administration exerted context-dependent effects on inflammasome-related gene expression, whereas probiotic co-administration attenuated several Cd-induced alterations, including partial normalization of BCL2 and IL-18 fold-change patterns and reduction of NLRP3 protein levels compared with the Cd group (p < 0.0001), although complete normalization was not achieved across all markers. Developmental exposure to a cafeteria diet was associated with alterations in splenic apoptotic, autophagy-associated, and inflammasome-related markers, consistent with immune dysregulation during the post-weaning period. Concurrent probiotic supplementation partially and context-dependently modulated several of these alterations.\n\nID: 42494073\nTitle: The ubiquitination of CD274 at MERCs enhances the anti-tumor immunity of cervical cancer.\nAbstract: Mitochondria-ER contact sites (MERCs) are crucial signaling hubs, but their role in anti-tumor immunity is unclear. This study revealed that the mitophagy regulator PRKN ubiquitinated CD274 at MERCs in human cervical cancer cells, a key mechanism for anti-tumor immunity. CD274 expression inversely correlated with PRKN in cervical cancer. Upon mitophagy activation, CD274 was recruited from ER to MERCs by PINK1, enhancing its interaction with PRKN. PRKN then ubiquitinated CD274 at residues K89 and K105 within its extracellular domain. Functionally, a ubiquitination-deficient CD274 mutant promoted anaerobic glycolysis and MTOR signaling, accelerating cancer cell growth. Coculture with ubiquitination-deficient CD274 mutant-expressing cancer cells increased the CD8+ T-cells' exhaustion. Single-cell RNA sequencing of mouse tumors showed the expansion of the exhausted CD8+ T cells and myeloid-derived suppressor cells (MDSCs) with ubiquitination-deficient CD274 mutation. In vivo, a ubiquitination-deficient CD274 mutant accelerated tumor growth and reduced the therapy efficacy of immune checkpoint inhibitors. Conversely, clinical sample analysis showed that CD274 localization at MERCs or its ubiquitination levels were closely associated with the improved immunotherapy efficacy. Thus, mitophagy-dependent recruitment of CD274 to MERCs for PRKN-mediated ubiquitination is a novel pathway that activates the anti-tumor immunity and improves the immunotherapy efficacy, presenting a promising strategic target for cervical cancer treatment.Abbreviations: CCCP, carbonyl cyanide m-chlorophenylhydrazone; CD, cluster of differentiation; CHX, cycloheximide; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GZMB, granzyme B; IFNG, interferon gamma; LDHA, lactate dehygrogenase A; MAP1LC3, microtubule-associated protein 1 light chain 3; MFN2, mitofusin 2; MHC, major histocompatibility complex; MTOR, mechanistic target of rapamycin kinase; OCR, oxygen consumption rate; PBMC, peripheral blood mononuclear cell; PDCD1, programmed cell death 1; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PKM, pyruvate kinase, muscle; RPS6, ribosomal protein S6; TNF, tumor necrosis factor; TME, tumor microenvironment.\n\nID: 42494065\nTitle: IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.\nAbstract: Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and \u03b3\u03b4 T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3\u03b2-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.\n\nID: 42494062\nTitle: CX3CR1+ macrophages aggravate doxorubicin-induced cardiomyopathy by impairing cardiac mitophagy via the CSF1R-PARP1-IL1B axis.\nAbstract: Doxorubicin is a widely used chemotherapeutic agent, but its clinical application is hindered by severe cardiotoxicity. Among immune cells, Cx3cr1+ macrophages have emerged as key regulators of cardiovascular disease, with their development and maturation tightly controlled by CSF1R (colony stimulating factor 1 receptor). Using multi-omics sequencing, we observed a marked expansion of Cx3cr1+ macrophages in doxorubicin-induced cardiomyopathy, yet their precise functional role in this pathological process has remained elusive. This study employed various genetically modified mouse models, including cell depletion models, lineage tracing models, and conditional gene knockout models targeting Cx3cr1+ macrophages, alongside transcriptomic sequencing, proteomic profiling, and multi-level in vivo and in vitro experiments to elucidate the role and mechanisms of Cx3cr1+ macrophages and their receptor CSF1R in doxorubicin-induced cardiac injury. We found that Cx3cr1+ macrophages are significantly enriched in hearts affected by doxorubicin-induced cardiomyopathy, and their depletion notably improves cardiac function. Further investigation revealed that in these macrophages, CSF1R competitively binds to the E3 ubiquitin ligase NEDD4, thereby inhibiting the ubiquitination and degradation of PARP1. This process promotes inflammasome activation and pyroptosis, driving massive IL1B secretion. IL1B directly suppresses cardiomyocyte mitophagy, disrupts energy metabolic homeostasis, and ultimately leads to cardiac dysfunction. Notably, the use of the CSF1R inhibitor PLX3397 or an IL1B-neutralizing antibody effectively halted these pathological processes and significantly improved cardiac function. In summary, this study unveils a novel mechanism through which Cx3cr1+ macrophages regulate cardiomyocyte function via the CSF1R-PARP1-IL1B-mitophagy signaling axis, providing a new theoretical foundation and intervention strategy for doxorubicin-induced cardiomyopathy targeted therapy.Abbreviations: BMDM: bone marrow-derived macrophages; CKMB: creatine kinase MB isoenzyme; CSF1R: colony stimulating factor 1 receptor; csf1r-cKO: csf1r conditional knockout; DIC: doxorubicin-induced cardiomyopathy; DOX: doxorubicin; HE: hematoxylin and eosin; HW:TL: heart weight:tibial length; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtuble-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; TNNT2/cTnT: troponin T2, cardiac; WGA: wheat germ agglutinin.\n\nID: 42494060\nTitle: The transsulfuration pathway metabolite \u03b1-ketobutyrate drives RIPK1-lactate axis-dependent autophagy to alleviate Staphylococcus aureus infection.\nAbstract: Breastfeeding anchors infant immunity and long-term health, but its benefits are threatened by Staphylococcus aureus (S. aureus) mastitis, an increasingly prevalent condition driven by antimicrobial resistance and therapeutic limitations. Beyond compromising maternal wellness, mastitis threatens the safety and continuity of breast milk, highlighting a critical need for innovative intervention strategies. Herein, we demonstrated that \u03b1\u2011ketobutyrate (\u03b1-KB), a metabolite of the transsulfuration pathway, mitigated S. aureus\u2011induced inflammation, oxidative stress, and blood-milk barrier (BMB) disruption both in vivo and in vitro. \u03b1\u2011KB enhanced macroautophagic/autophagic responses, marked by increased ATG5, BECN1 (beclin 1), and LC3-II:LC3-I conversion and reduced SQSTM1/p62, through a RIPK1-lactate-TFEB axis. Specifically, it directly bound and stabilized RIPK1, elevated lactate production, and drove TFEB nuclear translocation to activate macroautophagy/autophagy and promote intracellular bacterial clearance. Molecular docking and molecular dynamics simulations suggested stable \u03b1\u2011KB and RIPK1 binding via hydrophobic and hydrogen bond interactions; RIPK1 knockout abolished \u03b1\u2011KB-induced autophagy and lactate generation, effects rescued by lactate supplementation. This study identifies a novel immunometabolic circuit linking a metabolite to RIPK1-lactate-TFEB-mediated autophagy, offering therapeutic potential against antibiotic\u2011resistant S. aureus mastitis and presenting a new paradigm for safeguarding breastfeeding quality and infant health.\n\nID: 42493642\nTitle: The role of E3 ubiquitin ligases in selective types of macroautophagy.\nAbstract: In contrast to the ubiquitin (Ub)-proteasome-system, which only degrades individual proteins, macroautophagy can eliminate protein complexes or aggregates, organelles and even pathogens. Terms such as mitophagy, aggrephagy, lysophagy and xenophagy have been coined based on the targeted substrate. In Ub-dependent selective macroautophagy, cargo selectivity is specified by E3 Ub ligases that append Ub chains that in turn are recognized by selective autophagy receptors (SARs), driving sequestration into autophagosomes. While several Ub-dependent SARs have been identified and characterized, the E3 Ub ligases that ultimately decide target fate remain poorly studied. In this review, we summarize what is known about the E3 Ub ligases involved in selective macroautophagy, with a particular emphasis on the degradation of mitochondria, protein aggregates, lysosomes and pathogens. A better characterization of these enzymes could improve therapeutic strategies for targeted degradation in acute and chronic diseases.\n\nID: 42493297\nTitle: Autophagy in gastrointestinal cancers: Therapeutic and biological perspectives.\nAbstract: Gastrointestinal (GI) neoplasms are among the most common and lethal tumors around the world. In spite of the introduction of multiple conventional therapeutics for GI tumors, the treatment of these cancers is challenging. Moreover, they are able to mediate resistance to therapeutics. Therefore, the novel therapeutics should be developed for the treatment of GI tumors based on the underlying mechanisms. Autophagy is a programmed cell death mechanism dysregulated in human cancers and it is a potential therapeutic target. In the current review, a special focus is placed on the role of autophagy in GI neoplasms. The current studies have highlighted the fact that genomic and epigenetic factors can participate in the regulation of autophagy in GI tumors. Autophagy can exert protective function to enhance survival of cancer cells, while it decreases apoptosis, ferroptosis and other cell death mechanisms. On the other hand, the pro-death autophagy impairs the progression of GI tumors. In order to regulate autophagy in GI tumor therapy, the studies have focused on the development of drugs (synthetic drugs and natural compounds) along with nanoparticles for the autophagy modulation in GI cancer therapy. The autophagy-related factors can be considered as prognostic and diagnostic factors in GI tumors.\n\nID: 42493092\nTitle: Plasma-engineered chitosan couples red-light bioenergetics to diabetic wound regeneration through programmable microenvironments.\nAbstract: Diabetic wounds remain trapped in a non-healing loop driven by oxidative stress, impaired bioenergetics, and persistent inflammation. Here, we report a cold atmospheric plasma (CAP)-engineered chitosan-microalgae (CS-CHL) photobioactive dressing that converts a carbohydrate matrix into a programmable photosynthetic interface for wearable 660-nm activation. CAP remodeled the CS microenvironment in a duration-dependent manner, as verified by FTIR/XRD/NMR, and yielded a distinct optimum at 30\u00a0s with the most favorable polymer reorganization and coupling to CHL. This \"just-right\" window tuned photochemical branching under red light, showing the strongest oxygen-sensitive response as reflected by the lowest O\u2082 quenching index (~66.3%, indicating the greatest probe quenching and thus higher O\u2082 availability), while simultaneously enhancing reductive bioenergetic outputs, including hydrogen production (~117.6%) and MPP-Production (~116.4%), accompanied by the strongest light-responsive electrochemical signal. In an STZ-induced diabetic full-thickness wound model, CS-CHL\u00a0+\u00a0660\u00a0nm accelerated macroscopic wound closure versus wound-only and CS controls, while systemic hematological indices remained comparable across groups. Mechanistic tissue profiling further supported coordinated inflammation suppression, angiogenic/regenerative recovery, ROS reduction, mitochondrial functional restoration, and activation of mitophagy/autophagy-associated pathways. Collectively, CAP-tuned carbohydrate microenvironments provide a powerful route to program microalgal photobioenergetics and enable light-assisted diabetic wound repair.\n\nID: 42493063\nTitle: Cell autophagy promotes nucleopolyhedrovirus infection in the fall armyworm.\nAbstract: Pathogens, such as nucleopolyhedroviruses (NPVs), are promising biological control agents for lepidopteran pests to protect crops. However, a major drawback, their field application is limited by slower virulence compared with chemical insecticides. Modulating host pathways to enhance viral infectivity offers a potential strategy for improving NPV-based biocontrol. In this study, the expression level of NADH:ubiquinone oxidoreductase core subunit S8 (Ndufs8) was upregulated in the insect midgut following Spodoptera frugiperda NPV (SfNPV) infection. Silencing Ndufs8 impaired mitochondrial function, increased oxidative stress, and activated autophagy, but had no significant adverse effects on larval development and survival. The Ndufs8-autophagy cascade subsequently promoted SfNPV replication in insects. Co-feeding larvae with SfNPV and nanocarrier-delivered double-stranded RNA targeting Ndufs8 (dsNdufs8) accelerated insect death compared with the virus alone, demonstrating the enhanced virulence. Furthermore, bacterially expressed short hairpin RNA against Ndufs8 (shNdufs8), followed with nanocarrier delivery, achieved effective gene silencing and increased insect mortality comparable to synthetic dsNdufs8, supporting the potential field application for scalable RNA delivery. Our findings elucidate the function of a host responsive gene in the virus-host interaction. The combined use of dsNdufs8/shNdufs8 with SfNPV highlights a practical and scalable strategy to integrate RNA interference with pathogens to improve the biocontrol efficacy against insect pests.\n\nID: 42492782\nTitle: The mechanism by which long-term exposure to TDCIPP promotes cognitive impairment in 3\u00d7Tg-AD mice: insights from multi-omics studies.\nAbstract: Tri(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate ester that has the potential to adversely affect human health. Although previous studies have closely associated TDCIPP with cognitive impairment, the underlying mechanisms remain unclear. To elucidate the neurotoxic effects of TDCIPP and its mechanistic contribution to cognitive impairment in 3\u00d7Tg-AD mice, a multi-omics approach incorporating proteomics, untargeted metabolomics, and 16S ribosomal RNA (rRNA) gene sequencing was employed to evaluate the impact of TDCIPP exposure on neurobehavioral function. TDCIPP exposure promoted cognitive impairment in 3\u00d7Tg-AD mice. Proteomic analyses revealed that this promotion is associated with disturbances in the hippocampal mitochondrial autophagy pathway. Furthermore, TDCIPP may interfere with the PINK1/Parkin-mediated mitophagy pathway at the functional level, without altering PINK1 protein abundance. Untargeted metabolomic analysis of urine samples demonstrated that TDCIPP exposure altered the metabolic profile of 3\u00d7Tg-AD mice, with 58 metabolites upregulated and 11 downregulated. Additionally, 16S rRNA sequencing revealed substantial modifications in gut microbiome composition following exposure to TDCIPP. Notably, significant correlations were identified between the perturbed bacterial genera and the differential metabolites. In conclusion, exposure to TDCIPP promotes cognitive impairment in 3\u00d7Tg-AD mice, which is associated with the interference with the PINK1/Parkin-mediated mitophagy pathway, as well as alterations in the urinary metabolome and gut microbiota. These findings suggest the potential to mitigate such cognitive impairment by targeting the microbiota-gut-brain axis.\n\nID: 42492693\nTitle: Necroptosis and Cellular Stress Characterize Immune and Endothelial Dysfunction in Long COVID.\nAbstract: Long COVID, or Post-Acute Sequelae of SARS-CoV-2 infection (PASC), affects a significant proportion of COVID-19 survivors and is associated with persistent fatigue, dysautonomia, and cardiovascular complications. The cellular mechanisms underlying these chronic symptoms remain incompletely understood. Investigate immune and endothelial cell dysfunction, with a focus on cell stress and death pathways, in individuals with Long COVID compared to matched infection-recovered controls. We conducted a cross-sectional study at the University of Miami Miller School of Medicine and the Miami VA Healthcare System enrolling adults who met WHO criteria for Long COVID and age- and sex-matched controls with no history of Long COVID symptoms were recruited. Clinical assessments included COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm), Composite Autonomic Symptoms Score (COMPASS-31), heart rate variability (HRV), and vascular reactivity index (VRI). Peripheral blood was analyzed by spectral flow cytometry to characterize immune cell and circulating endothelial cell (CEC) populations and their expression of markers related to necroptosis (pMLKL), autophagy (LC3), hypoxia (HIF1-1\u03b1), and neutrophil extracellular traps (MPO, CitH3, NE). Long COVID patients (n=73) showed significantly higher Long COVID symptom scores compared to controls (n=41), along with impaired HRV and endothelial reactivity. Flow cytometry revealed increased expression of pMLKL, and LC3 in classical and non-classical monocytes, neutrophils, and eosinophils. CECs from Long COVID participants were substantially increased and demonstrated marked activation of necroptosis and autophagy pathways. These findings were accompanied by increased monocyte-platelet and CEC-platelet aggregates, consistent with a prothrombotic state. Elevated pMLKL expression in CECs strongly correlated with symptom severity and autonomic dysfunction. Our findings demonstrate that Long COVID is characterized by persistent inflammation and endothelial stress, involving necroptosis, and autophagy pathways. These mechanisms may contribute to chronic vascular and autonomic dysfunction in Long COVID patients. Targeting these stress and death signaling pathways may offer novel therapeutic strategies to mitigate the long-term consequences of SARS-CoV-2 infection.\n\nID: 42492624\nTitle: 2-Amino-5-hydroxyhexanoic acid mitigates diabetes-induced skeletal muscle atrophy by preserving protein homeostasis.\nAbstract: 2-Amino-5-hydroxy-hexanoic acid (2-AHA), an unusual amino acid isolated from Crotalaria juncea seeds, has been reported to exhibit antioxidant and antidyslipidemic activities. However, its role in maintaining skeletal muscle integrity under diabetic condition remains unexplored. The present study aimed to investigate the protective effects of 2-AHA against diabetes-induced skeletal muscle atrophy using in vitro (L6 myotubes) and in vivo (streptozotocin-induced diabetic rats) models. In L6 myotubes, 2-AHA treatment attenuated high glucose-induced atrophy features by suppressing muscle atrophy markers, increasing myotube diameter, surface area, and myosin heavy chain (MHC) expression, and inhibiting ubiquitin-proteasome-mediated protein degradation. In diabetic rats, 2-AHA administration improved body weight, lean mass, and muscle cross-sectional area, while enhancing grip strength and rotarod performance. Mechanistically, 2-AHA prevented muscle loss by inhibiting ubiquitin-proteasome- and autophagy-mediated protein degradation, concomitant with activation of AKT-mTOR pathway. Findings underscore the protective effects of 2-AHA against diabetes-induced skeletal muscle atrophy via regulating protein synthesis and protein degradation, and reveal its therapeutic implication to safeguard diabetes-associated skeletal muscle atrophy.\n\nID: 42492605\nTitle: Exosomes from bone marrow mesenchymal stem cells inhibit osteoclast differentiation and alleviate osteoporosis via RBM15B/YAP1 to induce autophagy.\nAbstract: Osteoporosis develops primarily as a result of an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Bone marrow mesenchymal stem cells-derived-exosomes (BMSCs-Exos) regulate osteoclast differentiation and osteoporosis in recent studies. But the mechanisms are still unclear. This research aimed to explore the mechanisms of BMSCs-Exos in osteoclast differentiation and osteoporosis. Exosomes were extracted from BMSCs. THP-1 cells were cultured and treated with BMSCs-Exos. Osteoclast- and autophagy-related gene expression was assessed by qPCR and Western blot, the regulation of YAP1 by RBM15B was analyzed by MeRIP and RNA pull-down, osteoclast differentiation was detected by TRAP staining. HE staining, immunohistochemical staining and micro-CT were employed to assess the impact of BMSCs-Exos on osteoporosis. BMSCs-Exos were internalized by THP-1 cells, promoted YAP1 expression and autophagy, and inhibited osteoclast differentiation. Silencing of YAP1 in THP-1 cells reversed BMSCs-Exos-induced autophagy and the inhibition of osteoclast differentiation; conversely, YAP1 overexpression produced opposite effects. BMSCs-Exos-delivered RBM15B promoted m6A methylation modification of YAP1. Silencing of RBM15B in BMSCs blocked the impact of BMSCs-Exos on autophagy and osteoclast differentiation, whereas RBM15B overexpression exerted opposing influences. Furthermore, BMSCs-Exos suppressed osteoclast differentiation and alleviated osteoporosis in vivo through RBM15B/YAP1 mediated autophagy. BMSCs-Exos promoted m6A methylation modification of YAP1 by delivering RBM15B mRNA to enhance YAP1 RNA stability, promoted autophagy, and inhibited osteoclast differentiation and alleviated osteoporosis.\n\nID: 42492603\nTitle: Neonatal propofol exposure induces region-specific neurotoxic proteomic signatures in mouse cortex and hippocampus.\nAbstract: Neonatal propofol exposure has been implicated in long-term neurodevelopmental impairments; however, region-specific molecular mechanisms remain unclear. This study examined region-specific proteomic alterations in exosome-enriched small extracellular vesicles (exosome-enriched sEVs) from the cortex and hippocampus induced by neonatal propofol exposure. Using a clinically relevant repeated-dose regimen, C57BL/6 mice received propofol (50\u202f\u202fmg/kg, P5-P7). At P21, exosome-enriched sEVs were isolated and analyzed by data-independent acquisition mass spectrometry. Candidate differentially expressed proteins (candidate DEPs) were defined by fold change (FC)\u202f\u2265\u202f1.5 or\u202f\u2264\u202f0.667 and nominal p\u202f<\u202f0.05, followed by Gene Ontology (GO), KEGG pathways, Cluster of Orthologous Groups (COG), and domain enrichment analyses. After Benjamini-Hochberg correction, no protein reached q\u202f<\u202f0.05, indicating that the exploratory findings were not significant. We identified 63 candidate DEPs in the hippocampus and 55 in the cortex. Hippocampal downregulated proteins enriched in synaptic vesicle cycling, oxidative phosphorylation, and apoptosis, suggesting synaptic-mitochondrial disruption; upregulated proteins associated with ER stress and chaperone-mediated autophagy, suggesting proteostatic adaptation. Cortical candidate DEPs reflected suppressed mitochondrial function alongside enhanced translation and cytoskeletal remodeling. These region- and direction-specific changes were consistently observed across all bioinformatic platforms. The hippocampus showed pronounced synaptic and mitochondrial alterations, while the cortex exhibited cytoskeletal changes and metabolic shifts. In conclusion, Propofol induces distinct neurotoxic proteomic signatures in the neonatal hippocampus and cortex, suggesting compartment-specific vulnerability and compensatory remodeling. Thus, exosome-enriched sEV proteomics offers a sensitive approach to detecting early anesthetic-induced neurodevelopmental disturbances.\n\nID: 42492365\nTitle: ARID1A regulates colorectal cancer metastasis through the AKT/mTOR/p70S6K pathway.\nAbstract: Colorectal cancer (CRC) is the most common malignant tumor of the digestive system. Exploring effective diagnostic markers and therapeutic targets has great significance for the diagnosis and treatment of CRC. ARID1A is frequently mutated in CRC, but its prognostic value for this disease remains controversial. Therefore, our aim was to explore the biological role of ARID1A in CRC and the underlying molecular mechanisms. The clinical relevance of ARID1A in CRC was evaluated using integrating multiple biological databases and a clinical cohort. In vitro and in vivo functional assays (CCK-8, colony formation, transwell, and xenograft models) assessed its tumor-modulating effects. Autophagy was examined via transmission electron microscopy and immunofluorescence, while western blotting quantified epithelial-mesenchymal transition, autophagy-related, and signaling pathway proteins. Based on CRC mutation data from TCGA-COAD and cBioPortal, the ARID1A mutation frequency was 14% and 16%, respectively. Survival analysis showed that the low-ARID1A-expression group had a poorer prognosis than the high-expression group. In vitro and in vivo studies showed that downregulation of ARID1A promotes various malignant biological behaviors of CRC cells, including proliferation, invasion, and metastasis. These phenotypic changes were accompanied by alterations in autophagy-related markers (such as decreased Beclin1 and LC3B, and increased p62) and activation of the AKT/mTOR/p70S6K signaling pathway. In addition, analyses of clinical samples indicated that low ARID1A expression is an independent risk factor for CRC recurrence and metastasis. In summary, ARID1A has a tumor-suppressive role in CRC. These data suggest that ARID1A expression is a potential biomarker for CRC, which could lead to novel clinical diagnostic and treatment approaches.\n\nID: 42492261\nTitle: A water-soluble Dendrobium officinale polysaccharide (DOPW) attenuates hepatic fibrosis via gut microbiota-mediated autophagy activation.\nAbstract: Hepatic fibrosis currently lacks effective therapies. DOPW, a water-soluble polysaccharide isolated from Dendrobium officinale, exerts anti-fibrotic effects, but its underlying mechanisms remain unclear. This study investigates whether DOPW attenuates fibrosis through a gut microbiota-dependent mechanism involving key microbial metabolites and the hepatic ERK1/2-autophagy signaling pathway. DOPW was structurally characterized. Its anti-fibrotic efficacy was evaluated in a mouse model of CCl\u2084-induced hepatic fibrosis and in TGF-\u03b21-induced LX-2 cells. Mechanistic investigations integrated transcriptomic analysis (RNA\u2011seq) with pharmacological targeting of ERK1/2 signaling and autophagy, combined with 16S rRNA sequencing and fecal microbiota transplantation (FMT) to assess the role of the gut microbiota. The key microbial metabolite butyrate was quantified in both colonic and hepatic tissues. DOPW is a polysaccharide (256 kDa) composed of glucose and mannose in a 5:1 molar ratio. DOPW dose-dependently alleviated hepatic fibrosis, reducing liver injury, inflammation, and collagen deposition (all p < 0.001). Mechanistically, DOPW activated hepatic stellate cell autophagy by inhibiting ERK1/2 signaling, as confirmed by rescue experiments with ERK1/2 modulators (all p < 0.05). Notably, DOPW enriched short-chain fatty acid-producing gut microbiota (Parabacteroides, Bifidobacterium, and Prevotella), elevated fecal butyrate by 2.11-fold (p = 0.0443), and reinforced intestinal barrier integrity (all p < 0.05). These microbiota and metabolite changes were associated with suppression of hepatic ERK1/2 phosphorylation. Antibiotic depletion abolished these effects, while FMT with DOPW-modified microbiota reproduced the anti-fibrotic benefits (all p < 0.05). DOPW attenuates hepatic fibrosis by remodeling gut microbiota to enhance short-chain fatty acid production and intestinal barrier integrity, with butyrate and ERK1/2-dependent autophagy emerging as key mediators of this gut-liver crosstalk. These findings position DOPW as a promising microbiota-targeted anti-fibrotic candidate.\n\nID: 42492242\nTitle: Lung-resident T-cell immunity dominates protection induced by an intranasal adenoviral nucleoprotein influenza vaccine.\nAbstract: Frequent antigenic drift in influenza viruses necessitates broadly protective vaccines. This study evaluated an intranasal adenoviral-vector vaccine expressing influenza A nucleoprotein (NP) fused to the autophagy-inducing peptide C5. A heterologous prime-boost regimen using chimpanzee and bovine adenoviral platforms induced strong NP-specific humoral and cellular immune responses in mice. High serum and lung IgG/IgA level were detected, accompanied by enhanced antibody-dependent cellular cytotoxicity. Cellular analyses revealed potent NP-specific cytokine responses and expansion of effector memory (TEM) and tissue-resident memory (TRM) T cells, particularly CD8+ TRM, in the lungs. Experiments using immune-deficient mice showed that B cells and CD8+ T cells independently contributed to early viral clearance. Adoptive transfer studies demonstrated that lung-derived T cells conferred the strongest heterosubtypic viral restriction, whereas systemic T cells and antibodies provided partial protection. Together, these findings highlight the critical role of lung-resident T cells in cross-protective viral control, supporting intranasal NP-based adenoviral vaccines as promising universal influenza vaccine candidates.\n\nID: 42492236\nTitle: PLIN3 knockdown enhances T cell-mediated cytotoxicity in non-small cell lung cancer via autophagy-dependent PD-L1 degradation.\nAbstract: Recently, immune checkpoint inhibitors (ICIs), especially those that targets PD-1/PD-L1, have significantly altered the treatment approach for NSCLC. Nevertheless, many patients experience different levels of resistance after receiving treatment with ICIs, which restrict their broader use in clinical practice. Therefore, to enhance the overall efficacy of ICIs, there is an immediate necessity to further explain the processes of immune evasion in NSCLC, especially the modulatory mechanism of PD-L1. IHC was used to evaluate the protein expression level of PLIN3 and PD-L1 in NSCLC tissues. The impact of PLIN3 on PD-L1 was analyzed in NCI-H1975 and NCI-H157 cells using western blot, flow cytometry and quantitative PCR (qPCR). Immunofluorescence was performed to examine the effect of PLIN3 on the autophagy level. The levels of Granzyme B (GZMB) and interferon-gamma (IFN-\u03b3) secreted by T cell were assessed. Bioinformatic analyses, including immune infiltration estimation and TIDE score, were performed using TCGA data. In this research, we discovered that elevated PLIN3 level was linked to decreased infiltration of CD4+ and CD8+ T cell, a higher TIDE score, and poorer immunotherapy response. In NSCLC tissues, there was a positive correlation between PLIN3 and PD-L1. Besides, the level of PLIN3 protein is significantly reduced in patients who achieve pathological complete response. In addition, PLIN3 knockdown markedly reduced the level of PD-L1 protein. Mechanistically, PLIN3 knockdown activated autophagy, and promoted PD-L1 degradation via the autophagic-lysosomal pathway, which consequently shortened its protein half-life. Furthermore, PLIN3 knockdown enhanced T-cell-mediated tumor killing and resulted in an increased secretion of the effector molecules, including granzyme B and IFN-\u03b3. In summary, our study has shown that targeting PLIN3 can induce autophagy, which promotes the degradation of PD-L1, ultimately leading to enhanced activation of T cells. This research is the first to investigate the function of PLIN3 in the immune microenvironment, revealing its critical function in immune evasion and highlighting its promise as a treatment target. This offers an innovative approach to enhance the efficacy of immunotherapy in lung cancer.\n\nID: 42492206\nTitle: Targeting the CD31 immunometabolic axis: Precision strategies for modulating T cell activation, migration, and autophagy.\nAbstract: CD31 (PECAM-1) is broadly expressed on endothelial cells, platelets, and immune cells, where it helps set thresholds for immune activation and coordinates energy use. This Review synthesizes evidence that CD31 is a key regulator of immunometabolic pathways relevant to metabolic disease. We outline how CD31 restrains T-cell activation, guides T-cell migration, and adjusts metabolic reprogramming by balancing glycolysis with mitochondrial function to fine-tune effector responses. We also describe how CD31-dependent signaling at the vascular-immune interface shapes tissue inflammation in obesity, diabetes, and atherosclerosis. Both membrane CD31 and its soluble form (sCD31) show promise as biomarkers and as therapeutic entry points, and we summarize emerging strategies to modulate this pathway. We highlight outstanding challenges including pathway complexity, context dependence, and inter-individual variability that must be addressed to achieve clinical translation. By linking molecular mechanisms to disease phenotypes, this Review positions CD31 as a unifying node connecting vascular and immune control with metabolism, pointing to testable avenues for precision treatment of metabolic inflammation.\n\nID: 42492188\nTitle: Ttyh3 ameliorates myocardial ischemia-reperfusion injury by activating Akt1 signaling to suppress apoptosis.\nAbstract: Myocardial ischemia-reperfusion injury (MIRI) poses significant challenges in cardiovascular therapeutics, with the molecular mechanisms underlying cardiomyocyte apoptosis remaining incompletely understood. This study identifies Ttyh3 as a critical regulator of MIRI and delineates its mechanistic pathway. In vivo and in vitro models revealed that Ttyh3 expression was significantly downregulated following myocardial ischemia-reperfusion (IR) and hypoxia-reoxygenation (HR) injury. Overexpression of Ttyh3 via AAV9 in mice markedly improved cardiac function-evidenced by enhanced ejection fraction (EF) and fractional shortening (FS)-and reduced infarct size. Concurrently, Ttyh3 overexpression attenuated mitochondrial dysfunction and apoptosis, suppressing pro-apoptotic Bax/cleaved caspase-3 while upregulating anti-apoptotic Bcl2. In vitro HR models mirrored these findings, confirming Ttyh3's anti-apoptotic role. Mechanistic studies revealed an association between Ttyh3 and Akt1, accompanied by enhanced Akt1 phosphorylation. Crucially, AKT inhibition largely abolished Ttyh3-mediated protection, confirming Akt1 activation as pivotal. Further, Ttyh3 knockdown or overexpression modulated the chaperonin subunit Cct3, a novel regulator linked to apoptosis regulation. Silencing Cct3 reversed Ttyh3-induced Akt1 phosphorylation and cardioprotection, establishing a Ttyh3-Cct3-p-Akt1 axis as central to mitigating apoptosis and IR injury. Collectively, these findings unveil Ttyh3 as a modulator of Akt1 signaling via Cct3, offering a promising therapeutic target to attenuate MIRI-driven cardiomyocyte apoptosis and mitochondrial damage. This study provides novel insights into the molecular interplay governing cardiac IR injury and underscores Ttyh3's potential for clinical translation.\n\nID: 42492135\nTitle: Synthesis of N5-furoxan-functionalized pyrazolo[3,4-d]pyrimidinones as novel nonclassical DHFR/TS inhibitors with potential apoptotic and anti-migratory activity.\nAbstract: Dihydrofolate reductase (hDHFR) and thymidylate synthase (TS) are pivotal folate-cycle enzymes that synergistically regulate DNA biosynthesis and cancer cell proliferation. Herein, the design and synthesis of multifunctional N5-furoxan-based pyrazolo[3,4-d]pyrimidinones (MAHS-1-11) as putative first-in-class hDHFR and TS inhibitors are reported. Among the synthesized analogs, MAHS-3 and MAHS-4 emerged as the most potent broad-spectrum, dose-dependent antiproliferative agents against the NCI-USA 60 cell panel examined herein, displaying MGI% values of 62.79% and 63.37%, respectively, comparable to methotrexate (65.60%), with GI\u2085\u2080s ranging from 0.276 to 85.2\u00a0\u03bcM. Both compounds exhibited good-to-moderate cytostaticity, with TGIs ranging from 10.6 to 82.5\u00a0\u03bcM and predominantly non-lethal effects across most cancer types tested. Notably, MAHS-4 showed a consistent inhibitory pattern across the full NCI panel, affording subpanel GI\u2085\u2080 (MG-MID) values of 3.84-20.33\u00a0\u03bcM and an overall full-panel MG-MID of 13.76\u00a0\u03bcM, with pronounced activity against leukemia, NSCLC, renal, prostate, and breast cancer subpanels. Enzymatic assays revealed moderate hDHFR inhibition by MAHS-3 and MAHS-4 (IC\u2085\u2080\u00a0=\u00a052.60 and 83.53\u00a0\u03bcM, respectively), whereas both compounds demonstrated superior TS inhibition relative to 5-FU, with approximately 1.5- and 2.5-fold enhanced potency, respectively. Mechanistically, both analogs induced G2/M-stage arrest, upregulated p21/p27, and activated the intrinsic Cas-dependent apoptotic pathway, as evidenced by increased Bax, Cas-7, and Cas-9, alongside reduced Bcl-2 and PARP-1 expression. Furthermore, both compounds exerted pronounced anti-metastatic effects, markedly elevated intracellular NO levels, and induced autophagy-related cell death. Molecular modeling studies showed that both compounds adopt a tortuous L-shaped conformation via the alkyl linker, enabling favorable spatial overlay with reference inhibitors within the target binding pocket, and identified the 5-membered heterocyclic moiety and the C6 region as key optimization hotspots. Furthermore, both compounds complied with Lipinski's and Pfizer's drug-likeness criteria. Overall, MAHS-3 and MAHS-4 represent promising next-generation TS-targeted antifolate preliminary hit compounds demonstrating moderate hDHFR inhibitory activity and requiring substantial optimization and pharmacokinetic evaluation.\n\nID: 42492121\nTitle: African swine fever virus E301R protein promotes RIG-I autophagic degradation by enhancing RIG-I-sequestosome-1 interaction.\nAbstract: African swine fever is a highly contagious disease caused by African swine fever virus (ASFV). The immune evasion capabilities of ASFV are crucial for its efficient replication within cells. As a DNA virus, the molecular mechanisms by which ASFV evades the cGAS-STING pathway have been extensively studied. However, the mechanisms underlying the evasion of dsRNA-activated pathways remain unclear. In this study, we aimed to identify the immunosuppressive function of ASFV E301R protein. We identified that pE301R strongly inhibits retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling and suppresses IFN-I production. pE301R impedes RLR signaling by directly degrading RIG-I, and pharmacological inhibition of autophagy rescued pE301R-induced RIG-I degradation. pE301R degrades RIG-I by promoting its interaction with p62. The siRNA-mediated knockdown of p62 rescued pE301R-mediated RIG-I degradation. In summary, our study demonstrates that pE301R degrades RIG-I via the autophagy pathway, thereby suppressing IFN-I production and aiding ASFV in evading the host's innate immune response. This finding enriches our understanding of the molecular mechanisms underlying the escape of ASFV from the RLR signaling pathway.\n\nID: 42492067\nTitle: Leveraging peptides for targeted protein degradation.\nAbstract: Targeted protein degradation (TPD) technology, with a particular emphasis on proteolysis-targeting chimeras (PROTAC), has emerged as a pivotal advancement in the field of drug discovery. However, several challenges-including the identification of suitable ligands for traditionally undruggable proteins, issues related to poor solubility and permeability, nonspecific biodistribution, and off-target toxicity-have significantly hindered their clinical translation. Peptides, recognized for their ability to serve as promising ligands for broad molecular recognition, exhibit unique potential to address these limitations in TPD applications. Literature and related information were collected from online resources such as Google Scholar, Web of Science, PubMed, CNKI, Baidu Scholar, and X-mol. Recent advancements in peptide-mediated TPD have shown promise in overcoming these challenges as researchers focus on engineering highly selective peptides that enhance binding affinity for traditionally undruggable proteins while optimizing their solubility and permeability, with next-generation delivery systems also developed to reduce nonspecific biodistribution and off-target toxicity, thereby improving the therapeutic potential of peptide-based TPD approaches. This review summarizes recent advancements in peptide-based PROTAC development, focusing on innovative delivery strategies and methods for enhancing efficiency, while also offering insights into future prospects aimed at optimizing therapeutic precision and efficacy.\n\nID: 42491593\nTitle: The role of endoplasmic reticulum stress-mediated autophagy in cadmium-induced liver injury in rats.\nAbstract: Cadmium (Cd) is a widespread toxicant with high bioaccumulation potential. This study explores the interplay of endoplasmic reticulum stress (ERS), autophagy, and apoptosis in Cd-induced hepatotoxicity, focusing on whether ERS-driven autophagy protects against liver injury. Male SD rats (4\u202fweeks old, n\u202f=\u202f24) were acclimatized for 7\u202fdays and randomized into four groups receiving CdCl\u2082 at doses of 0, 0.5, 1, or 2\u202fmg/kg for 14 consecutive days. A second cohort (n\u202f=\u202f36) was similarly allocated to six groups: control, Cd, 4-PBA, Cd\u202f+\u202f4-PBA, CQ and Cd\u202f+\u202fCQ. All treatments were administered via daily intraperitoneal injection throughout the study. On day 14, blood and liver tissues were collected for analyses of liver function, hematological parameters, and histopathology. The expression of target factors was analyzed via qRT-PCR and Western blotting. Results indicate that Cd exposure causes liver injury and disordered hepatocyte morphology. ERS markers Grp78 and Caspase-12 and autophagy-related factors Beclin-1, Atg5, P62 and LC3 are upregulated at both mRNA and protein levels. The endoplasmic reticulum-phagy (ER-phagy) receptor FAM134B and the apoptosis effector cleaved Caspase3 are upregulated at the protein level. These findings indicate that Cd induces ERS, UPR activation, autophagy, reticulophagy, and apoptosis. The ERS inhibitor 4-PBA markedly attenuated Cd-induced hepatic injury. Compared with the Cd group, the Cd\u202f+\u202f4-PBA group showed decreased serum ALT and AST levels, as well as reduced RBC, WBC, MCH, and MCV counts. At the molecular level, mRNA and protein expression of ER stress markers Grp78, Caspase-12, PERK, eIF2\u03b1, ATF4, IRE1\u03b1, JNK, and ATF6 were all downregulated. Protein levels of the ER-phagy receptor FAM134B and the apoptosis effector cleaved Caspase-3 were also decreased. The autophagy inhibitor CQ aggravated such injury. Compared with the Cd group, the Cd\u202f+\u202fCQ group showed increased serum ALT and AST levels, as well as elevated RBC, MCH, and MCV counts. At the protein level, expression of the autophagy-related factors P62 and LC3, and the apoptosis effector cleaved Caspase-3 was significantly increased. These results show that Cd-induced ERS activates autophagy and reticulophagy mainly via the PERK, IRE1\u03b1, and ATF6 pathways, and this adaptive response clears autophagic substrates to alleviate hepatocyte damage.\n\nID: 42491325\nTitle: Stigmasterol-Mediated Targeting of Rho-Associated Coiled-Coil Protein Kinase 1 Ameliorates Diabetic Kidney Disease and Attenuates Renal Tubular Lipid Deposition.\nAbstract: Diabetic kidney disease (DKD) is identified as the major contributor to the development of end-stage renal disease, with its clinical incidence increasing. Emerging studies link DKD closely to renal lipid deposition, tubular injury, and glomerulosclerosis-pathological processes driven by renal lipid metabolism disorders that ultimately induce renal fibrosis. However, targeted therapeutics for renal lipid deposition are scarce. This study fills this research gap: first, clinical database analyses identified a positive correlation between up-regulated rho-associated coiled-coil protein kinase 1 (ROCK1) expression in renal tubules and progressive renal function deterioration in DKD patients, a finding recapitulated in DKD mouse models, which also exhibited renal tubular ROCK1 up-regulation and concomitant lipid accumulation; second, molecular docking, surface plasmon resonance, and cellular thermal shift assay confirm that the natural molecule stigmasterol (ST) binds to ROCK1 and inhibits its expression with a dose-dependent trend; and, third, in\u00a0vivo and in\u00a0vitro experiments demonstrate that ST alleviates lipid accumulation, mitochondrial damage, and renal fibrosis in DKD via the ROCK1/p38 mitogen-activated protein kinase/peroxisome proliferator-activated receptor \u03b1 axis. In conclusion, ST exerts direct renoprotective effects by regulating the ROCK1 pathway to improve renal lipid metabolism, reduce mitochondrial damage, and inhibit fibrosis, highlighting its potential as a novel ROCK1 inhibitor. This study identifies ST as a candidate for targeted intervention in DKD-related lipid metabolism, validates ROCK1 as a therapeutic target, provides an experimental basis for the DKD treatment strategy of \"targeting ROCK1 to synergistically improve lipid metabolism and mitochondrial function\", and opens new avenues for natural products in metabolism-related nephropathies.\n\nID: 42491232\nTitle: Autophagy as a multi-scale architect of fungal development and pathogenicity: membrane dynamics, multilayer regulation, and cell wall integrity crosstalk.\nAbstract: Autophagy is a conserved membrane-trafficking pathway traditionally viewed as a nonspecific nutrient recycling mechanism. However, recent advances across diverse fungal systems, from plant pathogens to human opportunistic fungi and entomopathogenic species, have revealed autophagy as a central regulatory hub that orchestrates fungal development, virulence, and host interaction at multiple biological scales. This review provides a comprehensive and critical synthesis of these emerging insights. At the nanoscale, the discussion explores how autophagosome biogenesis depends on the spatially precise delivery of PtdIns4P by oxysterol-binding proteins, the dual function of the TRAPPIII vesicle-tethering complex, and the retromer-mediated sorting of vacuolar proteases. At the organelle level, the interplay between selective autophagy (mitophagy, lipophagy, pexophagy) and a newly discovered layer of epitranscriptomic, transcriptional, and post-translational regulation, comprising m5C RNA methylation of core ATG transcripts, FOX transcription-factor-driven gene activation, and nuclear acetylation of Atg8, respectively, is examined. At the macroscale, the review highlights how autophagy-dependent cell death and ferroptosis cooperate to drive appressorium maturation in Magnaporthe oryzae, and presents direct biochemical evidence for crosstalk between the cell wall integrity MAPK cascade and the autophagy machinery, a paradigm that challenges the long-standing view of these pathways as parallel systems. Further discussion addresses how autophagy deficiency triggers Mincle-dependent host immunity in Cryptococcus neoformans and how entomopathogenic Cordyceps militaris co-opts autophagy for fruiting body morphogenesis. We emphasize that the direct biochemical evidence for several of these mechanisms, notably CWI-MAPK/Atg4 crosstalk and autophagy-ferroptosis coupling, currently derives largely from Magnaporthe oryzae, and we distinguish such established mechanisms from cross-species extrapolations throughout. Finally, Atg4 inhibitors are evaluated as a promising class of broad-spectrum antifungal agents, and key directions for future research, including spatiotemporal imaging, multi-omics validation, and translational antifungal strategies, are identified.\n\nID: 42496931\nTitle: CircGABRB2_006 Drives Malignant Progression and EMT in Papillary Thyroid Carcinoma via the miR-296-5p/FGFR1 Axis.\nAbstract: Circular RNAs (circRNAs) have emerged as important regulators of tumor progression; however, their roles in papillary thyroid carcinoma (PTC) remain incompletely understood. In this study, we investigated the expression, biological function, and molecular mechanism of circGABRB2_006 in PTC. CircGABRB2_006 was significantly upregulated in PTC tissues and cell lines and was associated with aggressive clinicopathological characteristics, including increased tumor number, larger tumor size, advanced TNM stage, and lymph node metastasis. Functional assays demonstrated that circGABRB2_006 promoted PTC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), tumor growth, and pulmonary metastasis, whereas its silencing exerted the opposite effects. Mechanistically, circGABRB2_006 predominantly localized in the cytoplasm and acted as a molecular sponge for miR-296-5p, thereby relieving miR-296-5p-mediated repression of fibroblast growth factor receptor 1 (FGFR1). Rescue experiments further confirmed that the oncogenic effects of circGABRB2_006 were largely dependent on the miR-296-5p/FGFR1 axis. Collectively, these findings demonstrate that circGABRB2_006 drives malignant progression of PTC through the miR-296-5p/FGFR1 signaling axis, highlighting its potential as a biomarker and therapeutic target in PTC.\n\nID: 42496889\nTitle: Systems pharmacology and targeted transcriptional profiling suggest the putative neuroprotective role of Leuconostoc mesenteroides in an in vitro Alzheimer's disease model.\nAbstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-beta (A\u03b2) accumulation, mitochondrial failure, and neuroinflammation. While probiotics show therapeutic potential via the gut brain axis, the molecular mechanisms remain poorly understood. This study investigated the neuroprotective potential of Leuconostoc mesenteroides lysate and its bioactive metabolites in an A\u03b2-induced SH-SY5Y neuroblastoma model. SH-SY5Y cells were challenged with A\u03b2 and treated with L. mesenteroides lysate. Neuroprotective effects were evaluated via ROS accumulation, SOD1, APOE, NOS2, and mitochondrial dynamics (MFF, OPA1) using qPCR and WB. Potential mechanisms of action were explored computationally through integrated genome mining (antiSMASH 7.0), molecular docking (CB-Dock2), and systems pharmacology analysis (STRING/KEGG/R-studio) to identify candidate metabolites and host targets. L. mesenteroides lysate significantly attenuated A\u03b2-induced ROS levels and upregulated SOD1, enhancing antioxidant capacity. The lysate effectively downregulated APOE expression and restored mitochondrial homeostasis by reducing mitochondrial fission (MFF) and promoting fusion (OPA1). In silico analysis predected phytoene as a primary bioactive metabolite with significant theoretical binding affinity for APOE. Systems biology mapping revealed highly significant enrichment in PPAR signaling and cholesterol metabolism pathways (FDR\u2009<\u200910\u207b\u2075). Specifically, Cellular Component analysis highlighted robust interactions within protein-lipid complexes (FDR\u2009=\u20091.98e-16). L. mesenteroides lysate counteracts A\u03b2-induced neurotoxicity by modulating oxidative stress and restoring mitochondrial bioenergetics. Collectively, our findings suggest a theoretical Phytoene-PPAR-APOE signaling axis as a predictive framework for the observed cellular effects. We emphasize that phytoene represents a predicted candidate metabolite requiring future chemical characterization and biological validation.\n\nID: 42496762\nTitle: Atranorin suppresses the LUCAT1/STAT3 axis to induce ferroptotic cell death in ovarian cancer.\nAbstract: Ovarian cancer remains the most lethal gynecological malignancy and represents a major cause of cancer-related mortality among women worldwide. Despite advances in therapeutic strategies, treatment efficacy is frequently limited by systemic toxicity, chemoresistance, and disease recurrence, highlighting the urgent need for novel, mechanism-based targeted therapies with improved safety profiles. In the present study, we investigated the anti-cancer activity of atranorin (ATR), a naturally derived small-molecule compound, with a particular focus on its ability to induce ferroptosis by modulation of the LUCAT1/STAT3 signaling axis. Human ovarian cancer cell lines (OVCAR-3 and SKOV-3) and normal ovarian surface epithelial (OSE) cells were employed to evaluate cytotoxic selectivity and mechanistic effects. ATR selectively inhibited proliferation of ovarian cancer cells while exerting minimal cytotoxicity toward normal OSE cells. Mechanistic analyses demonstrated that ATR significantly suppressed LUCAT1 and STAT3 expression at both mRNA and protein levels, as confirmed by qRT-PCR and Western blotting. Concomitantly, ATR upregulated ferroptosis-related genes and proteins. Biochemical assessments revealed increased intracellular reactive oxygen species (ROS), elevated malondialdehyde (MDA) and iron accumulation, and depletion of glutathione (GSH), collectively indicating activation of ferroptotic cell death. Furthermore, ATR significantly impaired migratory and invasive capacities of ovarian cancer cells. Collectively, our findings identify ATR as a compound capable of inducing biochemical features consistent with ferroptosis in ovarian cancer through suppression of the LUCAT1/STAT3 axis. These results uncover a previously uncharacterized mechanistic pathway underlying ATR-mediated anti-tumor effect and support its potential development as a targeted therapeutic candidate for ovarian cancer management.\n\nID: 42495648\nTitle: Electroacupuncture attenuates synovitis in knee osteoarthritis and is associated with modulation of the protein S-TAM (Axl/MerTK)-Rac1 signaling axis.\nAbstract: Synovitis, a core pathological feature of knee osteoarthritis (KOA), drives pain and disease progression via sustained inflammation and disrupted tissue homeostasis. Electroacupuncture (EA) shows clinical benefits in KOA management, yet its specific molecular mechanisms against synovitis remain incompletely defined. The Protein S-Tyro3, Axl, MerTK (TAM) pathway-particularly Axl/MerTK and downstream Rac1-constitutes a key efferocytosis-related and inflammation-resolving signaling axis. We hypothesized that EA alleviates KOA synovitis and is associated with restoration of this dysregulated pathway. Male Sprague-Dawley rats were randomly assigned to Control, KOA (anterior cruciate ligament transection, ACLT), and KOA-EA groups. After 1 month of model induction, the KOA-EA group received EA at GB34, SP10, ST36, and KI3 (30 min/day, 5 days/week for 12 weeks; sparse-dense waves: 3/15\u00a0Hz, 1 mA). We assessed cartilage histopathology (Mankin's/OARSI scores), synovitis (Krenn score), synovial apoptosis (TUNEL, Cleaved Caspase-3/F4/80 co-staining), serum cytokines (IL-1\u03b2, TNF-\u03b1, IL-10, TGF-\u03b21 via ELISA), and MMP13 expression (IHC). qRT-PCR was used to measure Pros1, Axl, Mertk, and Rac1 mRNA expression in synovium, while Western blot was used to measure Protein S, Axl, MerTK, and Rac1 protein expression; MMP13 in cartilage was assessed by both methods. ACLT successfully induced KOA, with severe cartilage degradation, synovial inflammation, elevated pro-inflammatory cytokines, and increased synovial apoptosis. EA significantly ameliorated cartilage damage (reduced Mankin's/OARSI scores, P <\u00a00.01), decreased MMP13 expression (P <\u00a00.05), attenuated synovitis (lower Krenn score, P <\u00a00.01), reduced synovial apoptosis (P\u00a0<\u00a00.001), and shifted the cytokine profile toward an anti-inflammatory pattern (reduced IL-1\u03b2/TNF-\u03b1 and increased IL-10/TGF-\u03b21, P <\u00a00.05). EA was also associated with reversal of the KOA-induced downregulation of Protein S-TAM-Rac1 axis-related molecules, with significantly increased synovial mRNA expression and partial restoration of protein expression. EA showed anti-inflammatory and chondroprotective effects in this KOA model and was associated with changes in synovial Protein S-TAM (Axl/MerTK)-Rac1 axis-related molecules, with stronger evidence at the mRNA level than at the protein level. These molecular changes may be related to apoptotic cell clearance-related processes and inflammation resolution.\n\nID: 42494469\nTitle: Reprogramming Glial Cell Metabolism via a tRNA Fragment Preserves Vision in Retinal Neurodegeneration.\nAbstract: Retinal neurodegeneration leads to progressive and irreversible vision loss driven by retinal ganglion cell (RGC) death, yet effective neuroprotective therapies remain lacking. Recent studies suggest that small non-coding RNAs play key roles in central nervous system injury, but their relevance to retinal neurodegeneration remains incompletely understood. Here, we identify a significant increase in 5'tiRNA-His-GTG, an ANG-generated tRNA-derived fragment, in mouse models of retinal neurodegeneration. Functionally, elevated 5'tiRNA-His-GTG promotes reactive gliosis and contributes to RGC degeneration through M\u00fcller cell-RGC crosstalk. Conversely, inhibition of 5'tiRNA-His-GTG attenuates glial activation, preserves RGC survival, and improves visual function and vision-dependent behaviors. Mechanistically, 5'tiRNA-His-GTG induces neurodegenerative changes by suppressing the LPCAT1-mediated phosphatidylcholine (PC) biosynthetic pathway and perturbing glycerophospholipid metabolism. Notably, restoration of LPCAT1 expression or PC levels reverses 5'tiRNA-His-GTG-induced neurodegeneration both in vitro and in vivo. These findings uncover a previously unrecognized 5'tiRNA-His-GTG-LPCAT1-PC regulatory pathway that contributes to retinal neurodegeneration. Collectively, our study identifies 5'tiRNA-His-GTG as a critical mediator of glial-driven neuroinflammation and neuronal loss, and highlights this signaling axis as a potential therapeutic target for retinal neurodegeneration.\n\nID: 42494341\nTitle: miR-129-5p Modulates the ZEB1/2 Signaling Axis to Suppress Palmitic Acid-Induced Epithelial-Mesenchymal Transition and Barrier Dysfunction in ARPE-19 Cells.\nAbstract: Proliferative vitreoretinopathy (PVR) is driven by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. While palmitic acid (PA) represents a potent metabolic stressor in the subretinal microenvironment, its impact on the microRNA (miRNA) landscape remains poorly defined. This study investigated the role of miR-129-5p in PA-induced transdifferentiation and evaluated the protective potential of ectopic miR-129-5p mimicry in ARPE-19 cells. Low-passage ARPE-19 cells were challenged with sublethal PA to induce lipotoxic stress. miR-129-5p levels were modulated using synthetic mimics under basal and stressed conditions. EMT progression was tracked using immunofluorescence for tight junction topology and transcription factor nuclear localization, Phalloidin-FITC cytoskeletal F-actin staining, and immunoblotting for hallmark epithelial (E-cadherin) and mesenchymal (\u03b1-smooth muscle actin, fibronectin) effectors. Functional shifts were evaluated via wound healing and paracellular macromolecular permeability assays. PA exposure triggered a myofibroblastic phenotype and significantly depleted the intracellular miR-129-5p pool, accompanied by parallel vesicle-independent extracellular efflux. Under unchallenged baseline, mimic delivery directly suppressed endogenous ZEB1/2 expression. Under lipid stress, miR-129-5p mimicry neutralized transdifferentiation, successfully restoring E-cadherin and counteracting core transcription factor upregulation (ZEB1, ZEB2, and Snail). Morphologically, mimicry prevented pericellular ZO-1 dissolution, suppressed ZEB2 nuclear translocation, and blocked contractile stress fiber assembly. Functionally, maintaining this miRNA node significantly attenuated PA-enhanced cell migration and rescued outer blood-retinal barrier homeostasis by suppressing paracellular macromolecular flux. miR-129-5p functions as an essential cell-autonomous posttranscriptional gatekeeper of RPE identity, cytoskeletal architecture, and barrier homeostasis. Targeted modulation of this posttranscriptional network offers a promising pharmacological framework for mitigating lipotoxicity-associated subretinal fibrosis in PVR.\n\nID: 42494306\nTitle: Ouabain Relieves Sleep Deprivation-Induced Anxiety-Like Behavior in Mice by Suppressing Hippocampal Neuroinflammation and Oxidative Stress.\nAbstract: Sleep insufficiency has become a global public health challenge and is closely associated with the onset of mood and anxiety disorders. Neuroinflammation and oxidative stress are considered key pathological substrates underlying these conditions. Ouabain is a prototypical cardiotonic glycoside and an endogenous ligand of Na+/K+-ATPase. In recent years, ouabain has been reported to exert anti-inflammatory and neuroprotective effects; however, whether it can ameliorate sleep deprivation (SD)-associated affective abnormalities remains unclear. Using a 72-h modified multiple-platform SD model in male ICR mice, we investigated whether low-dose ouabain administration (3 \u00b5g/kg, i.p.) alleviates anxiety-like behaviors, as assessed by the open field test, and mitigates hippocampal inflammatory (cytokine TNF-\u03b1, IL-1\u03b2, IL-4, and IL-10) and redox disturbances (T-AOC, SOD, GPx, MDA, and CAT), as measured by ELISA. In parallel, PLX5622 and pathway-specific modulators were employed to explore the potential mechanisms underlying the beneficial effects of ouabain. In this study, SD reduced center zone time in the open field by 56.05% without changing locomotor activity, increased hippocampal TNF-\u03b1, IL-1\u03b2, and MDA by 105.11%, 82.50%, and 89.82%, respectively, and decreased IL-4, IL-10, SOD, GPx, CAT, and T-AOC by 54.28%, 47.22%, 44.96%, 51.95%, 52.14%, and 46.20%, respectively. Administration of low-dose ouabain significantly reversed these changes. PLX5622-mediated microglial depletion produced a partially similar protective profile, and pharmacological interference with Src/p38 MAPK/NF-\u03baB-associated signaling attenuated the effect of ouabain. Collectively, these findings suggest that low-dose ouabain mitigates acute SD-induced anxiety-like behavior, at least in part by suppressing hippocampal neuroinflammation and oxidative stress, and identify a potential signaling axis for further investigation.\n\nID: 42494277\nTitle: miR-145-5p Targets KLF4 to Regulate the SIRT3/GPX4 Axis, Mediating Ferroptosis and Exacerbating Tubular Epithelial Cell Injury in Diabetic Nephropathy.\nAbstract: To investigate whether miR-145-5p regulates high-glucose-induced ferroptosis and injury in renal tubular epithelial cells through the KLF4/SIRT3/GPX4 signaling axis. Ferroptosis, a regulated form of iron-dependent cell death, has been increasingly implicated in DKD pathogenesis. The present investigation was designed to explore the functional significance and underlying molecular mechanisms of the miR-145-5p/KLF4/SIRT3/GPX4 signalling cascade in ferroptotic cell death of renal tubular epithelial cells during DKD. A high-glucose-stimulated in\u00a0vitro DKD model was constructed using human renal tubular epithelial cells (HK-2) exposed to 25.0\u2009mmol/L glucose. Gene and protein expression profiles were characterised through RT-qPCR, Western blotting and immunofluorescence staining. Cellular viability, apoptotic rates and ferroptosis-associated biomarkers were quantified using CCK-8 assay, flow cytometric analysis, ELISA and JC-1 mitochondrial probe, respectively. Molecular binding interactions were confirmed through dual luciferase reporter assays and co-immunoprecipitation experiments. Intracellular reduced glutathione (GSH) content and GPX4 enzymatic activity were additionally measured to evaluate the functional status of the antioxidant arm of ferroptosis. High glucose exposure triggered time-dependent cellular damage and ferroptotic responses in HK-2 cells, characterised by elevated miR-145-5p levels alongside diminished KLF4, SIRT3 and GPX4 expression. Forced expression of miR-145-5p aggravated cellular damage and ferroptotic phenotypes, whilst its functional suppression conferred cytoprotection. Mechanistic analyses demonstrated that miR-145-5p directly engages the 3'-UTR of KLF4 to repress its expression. Restoring KLF4 expression attenuated high-glucose-mediated cellular injury and enhanced SIRT3 and GPX4 levels. Co-immunoprecipitation assays verified a physical protein-protein association between KLF4 and SIRT3. Functionally, HG stimulation reduced intracellular GSH content and GPX4 enzymatic activity. These changes were aggravated by miR-145-5p overexpression but were partially reversed by miR-145-5p inhibition or KLF4 overexpression. In the context of hyperglycemia, miR-145-5p facilitates ferroptotic cell death in renal tubular epithelial cells through KLF4 suppression, consequently attenuating the SIRT3/GPX4 signalling cascade and worsening DKD-related cellular injury. This regulatory axis may constitute a promising molecular intervention target for DKD treatment.\n\nID: 42493478\nTitle: The E3 Ubiquitin Ligase RLIM Safeguards Oligodendrocyte Development and Myelination by Targeting SLC7A11 for Polyubiquitination to Regulate Ferroptotic Resistance.\nAbstract: In the central nervous system, oligodendrocytes (OLs) generate myelin sheaths to support rapid nerve impulse conduction. OL lineage cells, especially oligodendrocyte precursor cells (OPCs), feature high metabolic activity and are exposed to severe oxidative stress, but the protective mechanisms remain poorly understood. Here we show that RLIM, an E3 ubiquitin ligase linked to X-linked neurodevelopmental disorders, safeguards OL development via ferroptosis resistance. RLIM directly polyubiquitinates SLC7A11, a key cystine/glutamate antiporter for glutathione (GSH) synthesis, thereby sustaining SLC7A11 membrane localization. OL lineage-specific ablation of RLIM in mice reduces membrane SLC7A11, impairs OPC proliferation, and triggers ferroptosis and thus myelination defects, leading to motor, social, and cognitive deficits that mimic patient phenotypes. Most pathological RLIM missense variants disrupt SLC7A11 binding and/or polyubiquitination. Importantly, GSH supplementation rescues myelination defects and behavioral abnormalities in RLIM-deficient mice. These findings reveal that the RLIM-SLC7A11-GSH signaling axis governs ferroptosis resistance in OL lineage cells, implicates this pathway in RLIM-related neurodevelopmental disorders, and suggests GSH as a potential therapeutic strategy.\n\nID: 42492841\nTitle: Exercise attenuates atherosclerosis by inhibiting eWAT aging via targeting SIRT1/pyruvate carboxylase pathway.\nAbstract: Aging is the primary risk factor for atherosclerosis (AS). Epididymal white adipose tissue (eWAT) is a key driver of organismal aging and age-related diseases. Exercise is known to protect against AS, but the role of aging eWAT in this process remains unclear. To this end, we investigated whether exercise inhibits AS by regulating aging eWAT and elucidated the involved mechanisms. ApoE-/- and C57BL/6 mice were fed a high-fat diet (HFD) to mimic poor lifestyle habits and explore eWAT senescence evolution. We found eWAT is a senescence-susceptible organ, exhibiting time-dependent deterioration under unhealthy lifestyle conditions. Furthermore, eWAT transplantation experiments confirmed that aging eWAT accelerates AS progression in both local and distal vascular regions. Exercise significantly ameliorated HFD-induced eWAT remodelling and inflammation, thereby inhibiting AS progression. Bioinformatics and lipidomic analyses identified that SIRT1 is essential for the anti-senescent eWAT effects of exercise by suppressing pyruvate carboxylase (PC). Contrarily, SIRT1 downregulation in eWAT with adeno-associated virus (AAV) reversed the exercise protective effects. Similarly, senolytic treatment (dasatinib plus quercetin) or PC downregulation with AAV also attenuated eWAT aging and AS progression. Our results demonstrate that exercise attenuates unhealthy lifestyle-induced premature aging of eWAT delays the progression of associated AS by modulating the SIRT1/PC axis. Thus, targeting this signaling axis may represent a novel therapeutic strategy for preventing AS and could serve as a potential alternative to exercise intervention.\n\nID: 42491353\nTitle: Decidual macrophage-mediated ferroptosis in trophoblasts leads to recurrent spontaneous abortion.\nAbstract: Recurrent spontaneous abortion (RSA) poses a significant challenge to successful early pregnancy, and trophoblast cell ferroptosis is an important pathogenic mechanism of RSA. However, it remains unclear whether decidual macrophages, as key immune regulators at the maternal-fetal interface, participate in the regulation of ferroptosis in trophoblast cells. This study observed significant ferroptosis in the placental trophoblast cells of patients with RSA and aborted mice. Transcriptomic sequencing results revealed that decidual macrophages derived from patients with RSA significantly promoted trophoblast cell ferroptosis while simultaneously impairing trophoblast cell function. Mechanistically, silencing heme oxygenase 1 (HMOX1) in trophoblast cells effectively reversed ferroptosis and restored trophoblast cell function, which was inhibited by decidual macrophages derived from patients with RSA. Notably, decidual macrophages regulate trophoblast ferroptosis and function by secreting C-X-C motif chemokine ligand 2 (CXCL2). Furthermore, the nuclear factor kappa-B (NF-\u03baB) pathway was significantly enriched in trophoblast cells co-cultured with decidual macrophages derived from patients with RSA. Further reversal experiments indicated that the CXCL2/NF-\u03baB/HMOX1 signaling axis may be a crucial mechanism by which decidual macrophages regulate trophoblast cell ferroptosis and function in RSA. Our subsequent findings demonstrated that trophoblast cells co-cultured with RSA-derived decidual macrophages promoted pro-inflammatory polarization in macrophages. This effect was mediated by the interleukin-6 (IL-6) deficiency-inhibited janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. Finally, pharmacological analysis revealed Eriodictyol exhibits CXCL2-axis-associated protective effects in RSA. In conclusion, we observed that decidual macrophages in patients with RSA can induce ferroptosis in trophoblast cells, implying that targeting this mechanism may offer novel opportunities for reshaping maternal-fetal tolerance.\n\nID: 42491287\nTitle: Tryptophan-Enriched Lactobacillus rhamnosus GG-derived Nanovesicles Promote Alveolar Bone Regeneration through Macrophage Fatty Acid Oxidation.\nAbstract: Inflammatory bone loss represents a major clinical challenge, leading to irreversible tissue damage and impaired function. Probiotic-derived nanovesicles show immense potential as novel cell-free nanomedicines; however, the lack of clarity regarding their precise mechanism of action in bone tissue regeneration restricts their clinical application. This study utilized a ligature-induced periodontitis mouse model (in vivo) and in\u00a0vitro models, including macrophage functional assays and macrophage-osteoblast co-culture systems, to investigate the therapeutic effects and mechanism of Lactobacillus rhamnosus GG-derived extracellular vesicles (LEVs). In the periodontitis mouse model, LEVs effectively mitigated inflammatory infiltration and promoted alveolar bone regeneration. In\u00a0vitro studies demonstrated that LEVs enhance macrophage polarization toward a reparative (M2) phenotype. Mechanistically, we identify LEVs as bioactive nanocarriers that deliver tryptophan metabolites. Upon internalization by macrophages, these metabolites trigger a critical metabolic and phenotypic shift by activating the aryl hydrocarbon receptor (AhR). Further research revealed that this effect is mediated by the AhR/NAD(P)H:quinone oxidoreductase 1 (NQO1)/carnitine palmitoyltransferase 1A (CPT1A) signaling axis: AhR transcriptionally up-regulates NQO1, which critically inhibits the 26S proteasome-mediated degradation of CPT1A. The resulting sustained CPT1A expression dramatically boosts fatty acid oxidation, which is essential for driving the reparative macrophage phenotype. These findings highlight the critical role and molecular delivery mechanisms of probiotic-derived nanovesicles in ameliorating inflammatory bone loss via immunometabolic reprogramming, thereby providing new targets and a theoretical basis for their application as nanocarriers in regenerative biomaterials.\n\nID: 42491280\nTitle: Ischemic preconditioning promotes hepatic differentiation in human liver organoids.\nAbstract: Liver regeneration is essential for successful outcomes after liver transplantation. However, ischemia-reperfusion injury (IRI) remains a major determinant of graft dysfunction that can profoundly affect hepatic regenerative responses. Although ischemic stress has been implicated in both tissue damage and regenerative signaling, its direct impact on progenitor differentiation and hepatocyte maturation remains poorly understood, partly due to the lack of controllable human experimental models. In this study, we investigated how controlled ischemic stress influences hepatocyte differentiation and regenerative signaling using a human liver organoid (HLiO) model. Organoids were expanded as undifferentiated cultures and subjected to a stepwise differentiation protocol toward hepatocyte-like cells. An in vitro IRI model was generated by exposing organoids to 16\u00a0h of cold ischemia (O2 0%) followed by reperfusion under normoxic conditions (O2 20%). Molecular, imaging, and functional analyses were performed to evaluate progenitor status, hepatocyte differentiation, and the release of inflammatory mediators. Differentiation of HLiOs induced a shift from progenitor-associated gene expression toward hepatocyte-specific programs, accompanied by increased albumin secretion and expression of mature markers. Controlled ischemia caused a transient reduction in viability and triggered the release of High Mobility Group Box 1 (HMGB1), Interleukin 1 Beta (IL-1\u03b2), Interleukin 8 (IL-8), and Oxidized Low Density Lipoprotein Receptor 1 (LOX-1), followed by recovery during reperfusion. Notably, ischemic preconditioning enhanced hepatocyte maturation, characterized by stronger downregulation of progenitor markers, increased expression of Cytochrome P450 3A4 (CYP3A4), Hepatocyte Nuclear Factor 4 Alpha (HNF4A), Alpha-1 Antitrypsin (A1AT), and albumin, and improved functional output compared with standard differentiation. These findings suggest that sub-lethal ischemic stress may act as a regenerative stimulus, potentially mediated by a progenitor-associated HMGB1-LOX-1-IL-8 signaling axis. Despite the absence of non-parenchymal liver cells, this organoid platform provides a controllable system to study intrinsic regenerative responses to ischemia, and indicates that appropriately modulated ischemic cues might promote hepatocyte differentiation, and improve graft recovery after liver transplantation.\n\nID: 42491058\nTitle: The role of FGF19-FGFR4 signaling pathway in liver health and disease: Guardian or destroyer.\nAbstract: The fibroblast growth factor (FGF) 15/19-FGF receptor (FGFR) 4 signaling pathway is a crucial endocrine regulatory pathway within the FGF family. The FGF15/19-FGFR4 signaling pathway plays multiple key roles in the liver, involving core physiological processes such as metabolic regulation, bile acid homeostasis maintenance, and hepatocyte proliferation and repair, and is also closely related to the pathogenesis of various liver diseases. At present, targeted therapeutic strategies for the FGF19-FGFR4 signaling axis have shown significant therapeutic potential. Agonists that simulate the physiological functions of FGF19 have been proven to effectively regulate bile acid and lipid metabolism in metabolic diseases and improve liver steatosis and fibrosis. Meanwhile, drugs that selectively inhibit FGFR4 have also demonstrated positive anti-tumor activity in specific tumor types driven by FGF19 overexpression. Given the crucial role of FGF19-FGFR4, clarifying the key mechanisms of this pathway in both physiology and pathology, as well as summarizing targeted therapy, is of vital importance. This review highlights the key role of FGF15/19-FGFR4 signaling in regulating liver physiological functions and reveals how its abnormal expression contributes to the occurrence of benign and malignant liver diseases. In addition, this review points out the potential of FGF15/19-FGFR4 signaling as a biomarker in different liver diseases and briefly discusses the existing treatment strategies for this signaling pathway.\n\nID: 42490453\nTitle: Yersiniabactin-producing adherent-invasive Escherichia coli exploit host glycolysis to drive macrophage HIF-1\u03b1 stabilization.\nAbstract: The siderophore yersiniabactin (Ybt) produced by a subset of intestinal adherent-invasive Escherichia coli (AIEC) drive intestinal fibrosis in murine model of Crohn's disease (CD). This is linked to the Ybt-induced disruption of host metal homeostasis and activation of the hypoxia-inducible factor 1-alpha (HIF-1\u03b1) in macrophages. Elevated glycolytic activity has been documented in both intestinal tissues and macrophages from patients with CD, indicating that metabolic reprogramming is a characteristic feature of the disease. Here, we show that HIF-1\u03b1 stabilization by Ybt+ AIEC requires active host glycolysis. This effect is independent of Hif1a transcription and lipopolysaccharide stimulation and is not solely explained by intracellular bacterial load but instead relies on host metabolic activity. Mechanistically, Ybt+ AIEC activated the Akt-mTOR pathway to support HIF-1\u03b1 translation. Inhibition of glycolysis suppressed this signaling axis, reducing HIF-1\u03b1 translation and nuclear localization. Given the association between Ybt+ AIEC and fibrosis in CD, these findings suggest that targeting host glycolysis may limit AIEC-driven macrophage HIF-1\u03b1 activation and fibrotic progression in CD patients.\n\nID: 42490398\nTitle: The NPM1/p53 nucleolar stress signaling pathway promotes endometrial receptivity establishment in goats via the Wnt/\u03b2-catenin pathway.\nAbstract: In goats, embryo implantation is superficial, making endometrial receptivity a key determinant of pregnancy success. Although the NPM1/p53 nucleolar stress pathway is involved in endometrial receptivity in mice and humans, its role in ruminants remains unknown. Using early-pregnancy goat models, in vitro-induced goat endometrial epithelial cells (gEECs), and low-dose Actinomycin D (ActD) to trigger nucleolar stress, we investigated this signaling axis in goat endometrial receptivity. Compared with pre-receptive Day 10 endometrium, receptive Day 16 endometrium showed increased NPM1 expression in epithelial cells, accompanied by its translocation from the nucleolus to the nucleoplasm. Markers of nucleolar stress (p53, p21, MDM2) were upregulated, while pre-rRNA levels were reduced. In gEECs, low-dose ActD effectively activated the NPM1/p53 pathway, which was also activated during in vitro receptivity induction using estrogen, progesterone, and interferon-tau. Activation of this pathway by ActD increased receptivity markers (HOXA10, HOXA11, MSX1), recapitulating changes seen during receptivity induction, whereas Npm1 knockdown attenuated this effect. ActD treatment also activated Wnt/\u03b2-catenin signaling. Pretreatment with the Wnt/\u03b2-catenin inhibitor Adavivint markedly reduced ActD-induced upregulation of HOXA10 and HOXA11 proteins but did not affect p53 expression. Together, these results indicate that the NPM1/p53 nucleolar stress pathway promotes endometrial receptivity in goats, at least in part, through the Wnt/\u03b2-catenin pathway. This work expands understanding of endometrial receptivity in ruminants and provides a basis for further investigation of nucleolar stress in reproductive regulation.\n\nID: 42490384\nTitle: HUWE1 targets mitochondria via RMC1 to promote neurodevelopment.\nAbstract: The HECT-type E3 ubiquitin ligase HUWE1 is a critical regulator of protein homeostasis, genome stability, and neurodevelopment. Variants in HUWE1 are linked to X-linked intellectual disability (XLID), yet a significant number of HUWE1 variants are noncatalytic, leaving their disease mechanisms unresolved. Here, we identify an AMBRA1-RMC1-HUWE1 signaling axis that directs HUWE1-mediated ubiquitination to mitochondria to regulate neural development. In zebrafish, noncatalytic HUWE1 variants found in XLID patients (M375I, G660R, and H669Q) recapitulate key neurodevelopmental deficits, including impaired brain growth and motor neuron defects. Global ubiquitin profiling reveals that these variants selectively disrupt the ubiquitination of mitochondrial proteins without affecting nuclear substrates. Mechanistically, AMBRA1 acts as a mitochondrial scaffold that recruits RMC1, enabling HUWE1 localization to mitochondria through direct interaction with RMC1. Disruption of this recruitment by disease-associated HUWE1 variants prevents mitochondrial targeting and impairs mitochondrial substrate ubiquitination. Notably, Urolithin A treatment ameliorates neurodevelopmental phenotypes in HUWE1-deficient zebrafish. Together, our findings define an AMBRA1-organized mitochondrial recruitment pathway in which RMC1 links HUWE1 to mitochondria, explain noncatalytic HUWE1-associated XLID, and suggest mitochondrial quality-control enhancement as a potential therapeutic strategy.\n\nID: 42490363\nTitle: Integrating Multi-Omics Mendelian Randomization and Functional Validation to Identify Novel Apoptosis Regulators in Follicular Lymphoma.\nAbstract: IntroductionDysregulation of apoptosis is a hallmark of follicular lymphoma (FL), yet the causal genetic drivers remain incompletely understood. This study aimed to identify causal apoptosis-related genes in FL and validate their functional roles.MethodsWe conducted a multi-omics Mendelian randomization (MR) study, integrating summary statistics from a large-scale FL genome-wide association study with data on methylation (mQTL), expression (eQTL), and protein (pQTL) quantitative trait loci. Summary data-based MR (SMR) and colocalization analyses were used to identify candidate causal genes. Independent external transcriptomic cohorts were utilized to validate the gene correlations, and evaluate the clinical prognostic relevance of the identified candidates. Key findings were then validated in FL patient tissues using RT-qPCR, and the functional role and downstream molecular mechanisms of the top candidate gene were systematically characterized through in vitro phenotypic characterization, drug sensitivity testing, and mechanistic signaling analyses.ResultsOur MR analysis identified several genes with causal links to FL risk, with integrative analysis highlighting IER3IP1, PRKCZ, and CD40. Notably, PRKCZ and CD40 exhibited significant correlation, whereas IER3IP1 displayed an independent regulatory pattern. Clinical tissue validation confirmed that IER3IP1 mRNA levels were significantly elevated in FL patient tissues. Functional studies in an FL cell line demonstrated that IER3IP1 acts as an oncogene, promoting proliferation, colony formation, and migration while inhibiting apoptosis. Mechanistically, IER3IP1 depletion promoted FOXO1-mediated transcriptional upregulation of CD20 via the XBP1/FOXO1 signaling axis, which concomitantly activated the intrinsic apoptotic pathway and significantly enhanced the sensitivity of FL cells to Rituximab-mediated cytotoxicity and apoptosis.Additionally, survival analysis revealed that CD40 serves as a strong prognostic indicator, with its low expression correlated with poorer progression-free survival and overall survival in FL patients.ConclusionsThis study provides the genetic and functional evidence establishing IER3IP1 as a novel causal oncogene in the pathogenesis of FL. Our findings elucidate the critical role of the IER3IP1-mediated XBP1/FOXO1/CD20 axis in targeted therapy resistance, highlighting IER3IP1 as a promising therapeutic target to restore apoptotic activity and improve Rituximab sensitivity.\n\nID: 42489440\nTitle: The PDPK1-RSK2 axis as a potential convergent therapeutic vulnerability in B-cell lymphomas.\nAbstract: B-cell lymphomas (BCLs) are the most prevalent group of hematologic cancers, encompassing various subtypes, each with a distinct clinical course shaped by cell of origin, genetics, and etiology. Recent advances in subtype-specific immunochemotherapy, targeted therapies, and cellular immunotherapy have improved outcomes for BCLs; nonetheless, some cases remain resistant to existing treatments. To address these resistant disease states, especially across multiple subtypes, the development of new universal targeted therapies could be transformative. This review first highlights what distinguishes the PDPK1/RSK2 signaling axis, outlines its normal biological functions, and briefly examines its roles in solid tumors. It then narrows the focus to BCLs, supported by evidence from our research on pathway activation, functional dependence, prognostic value, and early-stage drug development. The PDPK1/RSK2 axis is activated in nearly all BCL subtypes and likely plays a significant role in disease development. This suggests the potential for treatments that work across subtypes, despite their genetic and phenotypic differences. Targeting a shared signaling pathway might help overcome resistance seen with traditional precision medicine and support the development of new therapies for rare disease subtypes. However, because current research remains preclinical, more work is necessary.\n\nID: 42489267\nTitle: A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.\nAbstract: Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500\u00a0000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.\n\nID: 42489147\nTitle: Mechanistic Insights Into the Anti-Constipation Potential of Xiaogan Jianwei Formula: Integration of HPLC-Q-TOF MS/MS, Network Pharmacology, In\u00a0Vivo Validation, and Gut Microbiota.\nAbstract: This study aims to explore the mechanism of action and potential bioactive constituents of Xiaogan Jianwei Formula (XG) in the treatment of constipation. The chemical constituents of XG and its absorbable components were characterized using HPLC-Q-TOF MS/MS, and network pharmacology was used to predict key targets and pathways, identifying the cAMP/PKA signaling pathway as a target pathway. In\u00a0vivo experiments were performed to evaluate anti-constipation effects, including measurements of fecal water content, intestinal transit rate, MUC2 expression, cAMP/PKA/AQP3 signaling, and gut microbiota composition via 16S rRNA sequencing. In total, 138 chemical constituents were identified from XG, of which 32 components were absorbable; flavonoids were the main active ingredients. Pharmacological studies showed that XG significantly increased fecal water content and intestinal transit rate in loperamide-induced constipated rats without affecting physiological parameters. XG upregulated the expression of cAMP, PKA, p-PKA, and AQP3 and restored MUC2 expression. Moreover, XG improved gut microbiota diversity, enriched beneficial bacteria such as Akkermansia, and reduced pathogenic taxa like Helicobacter and Campylobacterota. XG alleviates constipation by regulating the cAMP/PKA/AQP3 signaling axis and modulating the gut microbiota. This study provides a scientific basis for the clinical application of XG and supports its development as an effective medicine for constipation.\n\nID: 42488574\nTitle: Developmentally sensitive neuropharmacological effects of dexamethasone in neonatal bronchopulmonary dysplasia-associated brain injury via microglial Acod1-itaconate/IL-1\u03b2 signaling.\nAbstract: Bronchopulmonary dysplasia (BPD) in preterm infants is frequently accompanied by neurodevelopmental impairment, yet the central neuropharmacological actions of dexamethasone (DEX), a commonly used therapy for severe or evolving BPD, remain incompletely understood. In particular, whether DEX exerts timing-dependent neuroprotection in the developing brain and the mechanisms underlying such effects are unclear. We investigated the neuroprotective effects of DEX in a neonatal rat double-hit model combining prenatal maternal lipopolysaccharide exposure with postnatal hyperoxia. A tapered DEX regimen was initiated on postnatal day (P)1, P3, or P8 to evaluate the therapeutic window. Lung pathology, survival, hippocampal injury, microglial reactivity, behavioral outcomes, resting-state functional magnetic resonance imaging (rs-fMRI), targeted metabolomics, and microglia-neuron coculture experiments were used to characterize pharmacological efficacy and mechanism. Among the tested regimens, DEX initiated at P3 produced the most consistent protective effects, improving alveolar structure, survival, hippocampal pathology, and microglial reactivity. P3-initiated DEX also improved recognition memory, exploratory/anxiety-related behavior, spatial memory retention, and motor coordination, and was associated with partial restoration of hippocampal functional connectivity. At the molecular level, DEX partially restored hippocampal glutamate/GABA balance, reduced Synapsin I phosphorylation, and normalized VGLUT1/VGAT associated synaptic abnormalities. Mechanistically, microglia-derived IL-1\u03b2 promoted neuronal ERK/Syn1 activation, whereas DEX interrupted this inflammatory signaling axis in a microglia-neuron coculture system. Targeted metabolomics and perturbation experiments further showed that DEX increased Acod1-dependent itaconate reprogramming under inflammatory priming, thereby suppressing microglial IL-1\u03b2 and downstream neuronal P-Syn1/Syn1 signaling. These findings identify a developmentally sensitive therapeutic window for DEX neuroprotection in neonatal BPD-associated brain injury and suggest that microglial Acod1-itaconate-dependent regulation of IL-1\u03b2/ERK/Syn1 signaling contributes to its central protective effects. This study expands the pharmacological interpretation of DEX beyond pulmonary benefit and supports an immunometabolic framework for understanding corticosteroid actions in the developing brain.\n\nID: 42488558\nTitle: Nucleophosmin 1 proteins as potential therapeutic targets in non-communicable chronic inflammatory diseases: a review of pathophysiological mechanisms.\nAbstract: Nucleophosmin1 (NPM1) proteins, initially recognized as central guardians of nucleolar architecture and function, have recently been redefined as pivotal hubs that integrate diverse forms of chronic cellular stress signaling. Although the roles of NPM1 have been extensively elucidated in tumor biology, its broad involvement in non-communicable chronic inflammatory diseases (NCDs) remains insufficiently and unsystematically summarized. Here, we highlight NPM1 as a key sensor of stress-induced nucleolar disassembly, nucleocytoplasmic translocation, and p53 stabilization. In pathological conditions such as myocardial ischemia, endothelial dysfunction, atherosclerosis, and chemotherapy-associated cardiotoxicity, NPM1 exhibits pronounced context dependence functioning either to initiate cytoprotective responses or to promote inflammation and apoptosis. In parallel, NPM1 plays a central role in maintaining genomic stability by sequestering, mobilizing, and regulating essential enzymes across multiple DNA damage repair pathways, including base excision repair (BER) and translesion synthesis (TLS). Dysregulation of these functions is closely linked to chronic pathological processes driven by metabolic stress, oxidative stress, and proteotoxicity. Collectively, available evidence suggests that NPM1, as a core node of the nucleolus-nucleoplasm signaling axis, may constitute a common molecular pathological basis underlying multiple chronic inflammatory diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders. A deeper dissection of its post-translational modifications, stress-dependent subcellular re-localization, and interactions with partner proteins is expected to provide a novel conceptual framework and therapeutic avenues for the development of NPM1-based targeted interventions. Accordingly, this review synthesizes the core molecular mechanisms of the NPM1 in the maintenance of cellular homeostasis, including regulating nucleolar stress, DNA damage repair, and inflammation, We place a particular emphasis on how these baseline pathways translate into distinct functional phenotypes within the pathological processes of chronic diseases, including cardiovascular, metabolic, and neurodegenerative disorders.\n\nID: 42486819\nTitle: [Gastrodin alleviates hypobaric hypoxia-induced brain injury in rats by reducing neuronal ferroptosis via the P53/SLC7A11/GPX4 signaling axis].\nAbstract: To investigate the neuroprotective effect of gastrodin (GAS) against hypobaric hypoxia (HH)-induced brain injury in rats and the underlying mechanism. Twenty-four adult SD rats were randomized equally into normoxic control group, HH model group, low-dose (100 mg/kg) GAS group (HH+GAS-L group), and high-dose (200 mg/kg) GAS group (HH+GAS-H group). In the latter 3 groups, the rats were exposed to HH in a hypobaric oxygen chamber for 24 h to simulate the condition at an altitude of 6000 m, and GAS was administered intraperitoneally once daily for 7 days. Cerebral cortex tissues were collected for analysis of P53, SLC7A11, and GPX4 protein expressions using Western blotting and for determination of the levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ion (Fe\u00b2\u207a). In cultured HT22 neurons exposed to oxygen-glucose deprivation (OGD), the effects of GAS (500 \u03bcmol/L), nutlin-3 (a P53 agonist; 10 \u03bcmol/L) or their combination were examined on ferroptosis-related protein expressions, intracellular ROS, lipid peroxidation, MDA, GSH, cell viability, mitochondrial membrane potential, and Fe\u00b2\u207a levels. In the rat models of HH, GAS treatment significantly inhibited P53 expression, upregulated SLC7A11 and GPX4 proteins, markedly reduced Fe\u00b2\u207a, ROS, and MDA levels, and increased GSH content in the cerebral cortex. In cultured HT22 neurons, GAS treatment effectively alleviated OGD-induced cell ferroptosis as shown by decreased P53 expression, increased SLC7A11 and GPX4 expressions, and lowered levels of intracellular ROS generation, lipid peroxidation, and Fe\u00b2\u207a accumulation, along with obvious restoration of GSH levels, cell viability, and mitochondrial membrane potential. The protective effects of GAS was markedly attenuated by activation of the P53 pathway using nutlin-3. GAS produces neuroprotective effects against HH-induced brain injury in rats by inhibiting neuronal ferroptosis via regulating the P53/SLC7A11/GPX4 signaling pathway. \u76ee\u7684: \u7814\u7a76\u5929\u9ebb\u7d20\uff08GAS\uff09\u5bf9\u9ad8\u539f\u4f4e\u538b\u7f3a\u6c27\uff08HH\uff09\u6027\u8111\u635f\u4f24\u7684\u795e\u7ecf\u4fdd\u62a4\u4f5c\u7528\uff0c\u5e76\u63a2\u8ba8\u5176\u673a\u5236\u662f\u5426\u4e0e\u8c03\u8282P53/SLC7A11/GPX4\u4fe1\u53f7\u901a\u8def\u3001\u6291\u5236\u795e\u7ecf\u5143\u94c1\u6b7b\u4ea1\u76f8\u5173\u3002\u65b9\u6cd5: \u4f53\u5185\u5b9e\u9a8c\u9009\u53d624\u53ea\u6210\u5e74SD\u5927\u9f20\uff0c\u968f\u673a\u5206\u4e3a4\u7ec4\uff08n=6\uff09:\u5e38\u538b\u5e38\u6c27\u5bf9\u7167\u7ec4\uff08Nor\uff09\u3001\u4f4e\u538b\u7f3a\u6c27\u6a21\u578b\u7ec4\uff08HH\uff09\u3001\u5929\u9ebb\u7d20\u4f4e\u5242\u91cf\u7ec4\uff08HH+GAS-L\uff0c100 mg/kg\uff09\u3001\u5929\u9ebb\u7d20\u9ad8\u5242\u91cf\u7ec4\uff08HH+GAS-H\uff0c200 mg/kg\uff09\u3002\u9664\u5bf9\u7167\u7ec4\u5916\uff0c\u5176\u4f59\u5404\u7ec4\u5927\u9f20\u7f6e\u4e8e\u6a21\u62df\u6d77\u62d46000 m\u7684\u4f4e\u538b\u6c27\u8231\u4e2d\u6301\u7eed\u66b4\u973224 h\u4ee5\u5efa\u7acbHH\u6a21\u578b\u3002\u5929\u9ebb\u7d20\u4e8e\u9020\u6a21\u540e\u8179\u8154\u7ed9\u836f\uff0c1\u6b21/d\u3002\u53d6\u7b2c7\u5929\u7684\u8111\u76ae\u5c42\u8fdb\u884cWestern blotting\u68c0\u6d4bP53\u3001SLC7A11\u53caGPX4\u86cb\u767d\u8868\u8fbe\uff0c\u540c\u65f6\u6d4b\u5b9a\u7ec4\u7ec7\u5185\u6d3b\u6027\u6c27\u6807\u5fd7\u7269\uff08DHE\uff09\u3001\u4e19\u4e8c\u919b\uff08MDA\uff09\u3001\u8c37\u80f1\u7518\u80bd\uff08GSH\uff09\u53ca\u4e9a\u94c1\u79bb\u5b50\uff08Fe\u00b2\u207a\uff09\u7684\u542b\u91cf\u3002\u4f53\u5916\u57f9\u517bHT22\u795e\u7ecf\u5143\uff0c\u5206\u4e3a:\u5bf9\u7167\u7ec4\uff08Control\uff09\u3001\u6a21\u578b\u7ec4\uff08OGD\uff09\u3001\u5929\u9ebb\u7d20\u5e72\u9884\u7ec4\uff08OGD+GAS\uff0c500 \u03bcmol/L\uff09\u3001P53\u6fc0\u52a8\u5242\u7ec4\uff08OGD+Nutlin-3\uff0c10 \u03bcmol/L\uff09\u53ca\u8054\u5408\u5904\u7406\u7ec4\uff08OGD+GAS+Nutlin-3\uff09\u3002\u68c0\u6d4b\u6307\u6807\u5305\u62ec\u94c1\u6b7b\u4ea1\u76f8\u5173\u86cb\u767d\u8868\u8fbe\u3001\u7ec6\u80de\u5185\u6d3b\u6027\u6c27\uff08DCFH-DA\uff09\u3001\u8102\u8d28\u8fc7\u6c27\u5316\uff08BODIPY-C11\uff09\u3001MDA\u3001GSH\u3001\u7ec6\u80de\u5b58\u6d3b\u7387\uff08CCK-8\uff09\u3001\u7ebf\u7c92\u4f53\u819c\u7535\u4f4d\uff08JC-1\uff09\u53ca\u4e9a\u94c1\u79bb\u5b50\uff08FerroOrange\uff09\u3002\u7ed3\u679c: \u52a8\u7269\u5b9e\u9a8c\u663e\u793a\uff0c\u4e0eHH\u7ec4\u76f8\u6bd4\uff0c\u5929\u9ebb\u7d20\u663e\u8457\u6291\u5236P53\u8868\u8fbe\uff0c\u4e0a\u8c03SLC7A11\u4e0eGPX4\u86cb\u767d\u6c34\u5e73\uff08P<0.05\uff09\uff0c\u5e76\u663e\u8457\u964d\u4f4e\u8111\u76ae\u5c42\u7ec4\u7ec7Fe\u00b2\u207a\u3001ROS\u548cMDA\u542b\u91cf\uff0c\u63d0\u9ad8GSH\u6c34\u5e73\uff08P<0.05\uff09\u3002\u7ec6\u80de\u5b9e\u9a8c\u7ed3\u679c\u4e00\u81f4\uff0c\u5929\u9ebb\u7d20\u6709\u6548\u51cf\u8f7b\u4f4e\u538b\u7f3a\u6c27\u8bf1\u5bfc\u7684\u94c1\u6b7b\u4ea1\uff0c\u8868\u73b0\u4e3aP53\u8868\u8fbe\u4e0b\u964d\uff0cSLC7A11\u4e0eGPX4\u8868\u8fbe\u5347\u9ad8\uff08P<0.05\uff09\uff0c\u7ec6\u80de\u5185ROS\u751f\u6210\u3001\u8102\u8d28\u8fc7\u6c27\u5316\u548cFe\u00b2\u207a\u84c4\u79ef\u88ab\u6291\u5236\uff0c\u540c\u65f6GSH\u542b\u91cf\u3001\u7ec6\u80de\u6d3b\u6027\u548c\u7ebf\u7c92\u4f53\u819c\u7535\u4f4d\u663e\u8457\u6062\u590d\uff08P<0.05\uff09\u3002\u800c\u4f7f\u7528Nutlin-3\u6fc0\u6d3bP53\u4fe1\u53f7\u901a\u8def\u540e\uff0c\u5929\u9ebb\u7d20\u7684\u4fdd\u62a4\u4f5c\u7528\u88ab\u660e\u663e\u9006\u8f6c\uff08P<0.05\uff09\u3002\u7ed3\u8bba: \u5929\u9ebb\u7d20\u53ef\u80fd\u901a\u8fc7\u8c03\u63a7P53/SLC7A11/GPX4\u4fe1\u53f7\u901a\u8def\u6291\u5236\u795e\u7ecf\u5143\u94c1\u6b7b\u4ea1\uff0c\u4ece\u800c\u5bf9\u9ad8\u539f\u4f4e\u538b\u7f3a\u6c27\u6027\u8111\u635f\u4f24\u53d1\u6325\u795e\u7ecf\u4fdd\u62a4\u4f5c\u7528\u3002.\n\nID: 42486791\nTitle: A Glucocorticoid-KLF9-CHCHD10 Axis Governs Mitochondrial Resilience in Radiation-Induced Lung Injury.\nAbstract: Radiation-induced lung injury (RILI) is a major dose-limiting complication of thoracic radiotherapy. Although mitochondrial damage has been implicated in RILI, the endogenous transcriptional programs that restore mitochondrial structure and bioenergetic function after irradiation remain poorly defined. To identify radiation-sensitive mitochondrial regulators in type II alveolar epithelial cells (AT2), we integrated single-cell RNA sequencing data from irradiated lungs with weighted gene co-expression network analysis. Transcription factor prediction, multi-omics correlation analysis, and molecular docking were used to construct upstream regulatory networks. The functional relevance of the KLF9-CHCHD10 axis was validated using mitochondrial ultrastructure analysis, oxygen consumption assays, apoptosis detection, gene expression profiling, and CHCHD10 loss- and gain-of-function experiments performed in vitro and in\u00a0vivo. Single-cell transcriptomic profiling identified CHCHD10, a mitochondrial cristae-associated protein, as a central radiation-sensitive hub in AT2 cells. Irradiation reduced CHCHD10 expression and disrupted mitochondrial homeostasis, leading to mitochondrial fragmentation, impaired oxygen consumption, enhanced epithelial apoptosis, activation of the Ppia-CD147 inflammatory signaling axis, and suppression of PPAR\u03b3-associated metabolic homeostasis. Mechanistically, KLF9 directly activated CHCHD10 transcription, whereas irradiation suppressed the KLF9-CHCHD10 circuit. Restoration of this pathway by CHCHD10 overexpression or glucocorticoid intervention preserved mitochondrial cristae integrity, improved bioenergetic recovery, and enhanced epithelial cell survival. In vivo, lung-specific CHCHD10 knockdown aggravated radiation-induced parenchymal remodeling and fibrotic deposition and partially weakened the protective efficacy of glucocorticoids. This study defines a GC-KLF9-CHCHD10 axis that restores mitochondrial ultrastructure and bioenergetics after radiation, positioning mitochondrial resilience as an active epithelial protective program in RILI. Antioxid. Redox Signal. 00, 000-000.\n\nID: 42486346\nTitle: Multi-omics and artificial intelligence nominate PCLAF as a prognostic and druggable target for hepatitis B virus-associated hepatocellular carcinoma.\nAbstract: PCLAF (PCNA clamp-associated factor) is a protein involved in DNA replication and DNA repair. Aberrant PCLAF expression has been reported in multiple malignancies and is associated with tumor progression and poor clinical outcomes. However, the biological role of PCLAF in hepatocellular carcinoma (HCC) remains incompletely understood, particularly with respect to its relationship with the tumor immune microenvironment. Therefore, this study aimed to systematically investigate the clinical significance, biological functions, and therapeutic potential of PCLAF in HCC through integrated multi-omics analyses, experimental validation, and drug screening approaches. In this study, an integrative multi-omics framework was employed to systematically investigate the molecular characteristics and biological functions of PCLAF in hepatocellular carcinoma (HCC). Transcriptomic datasets from the GEO database (GSE83148 and GSE121248) and the TCGA-LIHC cohort were analyzed to identify differentially expressed genes, followed by protein-protein interaction network construction and machine learning algorithms to screen and validate key hub genes. Pan-cancer analysis, clinicopathological correlation analysis, survival analysis, and receiver operating characteristic (ROC) curve analysis were subsequently performed to evaluate the clinical significance of PCLAF. Single-cell RNA sequencing data (GSE202642) were analyzed to characterize the cellular heterogeneity of hepatitis B virus-associated HCC and identify PCLAF-associated cell populations. Functional module scoring and gene set enrichment analysis were performed to investigate the biological features of Cycling T cells. Spatial transcriptomic data (GSE245908) were integrated with deconvolution, cell-cell communication, and spatial regulatory analyses to explore the spatial distribution patterns and intercellular interactions associated with PCLAF. To identify potential therapeutic agents targeting PCLAF, virtual drug screening, molecular docking, and molecular dynamics simulations were conducted. Finally, clinical specimens and HCC cell lines were used for experimental validation. Immunohistochemistry, RT-qPCR, western blotting, colony formation, wound-healing, Transwell migration, and CCK-8 assays were performed to evaluate the effects of PCLAF on HCC cell proliferation and migration. Through integrated transcriptomic analysis, protein-protein interaction network construction, and machine learning approaches, PCLAF was identified as a key candidate gene associated with HCC. Pan-cancer and clinical analyses demonstrated that elevated PCLAF expression was associated with advanced tumor stage, higher pathological grade, and poor prognosis across multiple cancer types. Single-cell transcriptomic analysis revealed that PCLAF was predominantly enriched in Cycling T cells. Functional characterization showed that Cycling T cells exhibited a hyperproliferative but functionally restricted phenotype, characterized by enhanced proliferation accompanied by reduced activation and cytotoxicity. Spatial transcriptomic and cell-cell communication analyses further identified a potential epithelial cell-Cycling T cell interaction network, in which the MIF-CD74-CXCR4 signaling axis represented a major communication pathway. To explore therapeutic opportunities, AI-assisted drug screening, molecular docking, and molecular dynamics simulations were performed, leading to the identification of BRD-K12189280 as a promising candidate compound targeting PCLAF. Experimental validation confirmed that PCLAF was significantly overexpressed in HCC tissues, and its knockdown markedly inhibited the proliferation, migration, and viability of HCC cells in vitro. Our findings demonstrate that PCLAF is significantly upregulated in HBV-associated hepatocellular carcinoma and promotes malignant cellular phenotypes. Multi-omics analyses revealed a close association between PCLAF expression and a hyperproliferative but functionally restricted Cycling T-cell state, highlighting a potential link between tumor progression and immune microenvironment remodeling. These results identify PCLAF as a promising prognostic biomarker and therapeutic target in HCC, while BRD-K12189280 emerges as a potential candidate compound for future drug development.\n\nID: 42486063\nTitle: WLJP-025p, a pectic polysaccharide from Lonicera japonica Thunb., suppresses proliferation and cellular respiration in IHH-4 thyroid cancer cells through a Gal-3-associated FAK/SRC signaling pathway.\nAbstract: Lonicera japonica polysaccharides have been reported to possess anti-tumor potential, but their effects and mechanisms in thyroid cancer remain insufficiently defined. In this study, an acidic pectic polysaccharide, WLJP-025p (average molecular weight 23\u00a0kDa; purity 93.7%), was screened for selective anti-proliferative activity against IHH-4 papillary thyroid cancer cells. Based on the carbohydrate-recognition properties of galectin proteins and bioinformatics analysis of thyroid cancer datasets, Gal-3 was selected as a candidate WLJP-025p-interacting protein. Fluorescence spectroscopy and biolayer interferometry further supported a biochemical interaction between WLJP-025p and Gal-3. Functionally, WLJP-025p suppressed IHH-4 cells proliferation and migration, reduced Gal-3/FAK/SRC-associated signaling, and impaired glycolysis and mitochondrial respiration-related functional readouts as indicated by ECAR and OCR assays. In a nude mouse xenograft model, intratumoral WLJP-025p administration reduced tumor growth and downregulated Gal-3/FAK/SRC-associated protein signals in tumor tissue. These findings suggest that WLJP-025p suppresses IHH-4 thyroid cancer cell proliferation at least partly through a Gal-3-associated FAK/SRC signaling pathway and provide proof-of-concept evidence for further development of L. japonica polysaccharides as anti-tumor macromolecules.\n\nID: 42485885\nTitle: Hsa-mir-1293/GLI1/PTCH1 axis is involved in proliferation, migration, and EMT of laryngeal cancer.\nAbstract: This study aimed to investigate the specific role and molecular mechanisms of the transcription factor GLI1 and its upstream regulatory miRNA, hsa-mir-1293, in laryngeal cancer development, with a focus on elucidating the function of the hsa-mir-1293/GLI1/PTCH1 signaling axis in regulating laryngeal cancer cell proliferation, migration, and EMT. Differentially expressed miRNAs were screened from TCGA laryngeal cancer miRNA data, and the interaction between hsa-mir-1293 and GLI1 was validated using a dual luciferase reporter assay. The effects of hsa-mir-1293 on TU212 cell proliferation, clonal formation, and invasion were examined. The role of GLI1's downstream target, PTCH1, in cell proliferation, migration, and EMT was further investigated. Bioinformatics analysis identified hsa-mir-1293 as the most significantly down-regulated miRNA in laryngeal carcinoma, showing a negative correlation with GLI1 expression. Overexpression of hsa-mir-1293 suppressed TU212 cell proliferation, clonal formation, and invasion. Silencing GLI1 reduced PTCH1 expression, while PTCH1 overexpression promoted cell invasion, migration, and EMT. Hsa-mir-1293 targets GLI1, and the GLI1/PTCH1 axis plays a critical role in laryngeal cancer cell proliferation, migration, and EMT.\n\nID: 42485836\nTitle: COL1A1 regulates the progression of dry eye disease through metabolic reprogramming and inflammatory responses via the HIF1A/HK2 pathway.\nAbstract: Dry eye disease (DED) is a prevalent ocular surface disorder with complex pathogenesis involving glycolytic reprogramming and inflammation. This study aims to investigate whether collagen type I alpha 1 chain (COL1A1) modulates metabolic dysregulation and inflammatory responses in DED, and to evaluate its potential as a disease-modifying therapeutic target through the hypoxia-inducible factor-1\u03b1 (HIF1A)/hexokinase 2 (HK2) pathway. In vitro, human corneal epithelial cells (HCEs) were exposed to hyperosmotic stress; COL1A1 overexpression and COL1A1-HIF1A co-overexpression were performed. In vivo, a DED mouse model was induced via scopolamine injection and low humidity, with adeno-associated virus (AAV)-mediated Col1a1/Hif1a overexpression. Assessments included qRT-PCR, Western blotting, ELISA, lactate assay, extracellular acidification rate (ECAR) measurement, transepithelial electrical resistance (TEER), tear secretion test, and Periodic Acid-Schiff (PAS) staining. In a scopolamine-induced DED mouse model, Col1a1 overexpression significantly restored tear secretion and increased conjunctival goblet cell density, both of which were markedly impaired under disease conditions. At the cellular level, COL1A1 expression was downregulated under hyperosmotic stress, whereas HIF1A/HK2 signaling and glycolytic activity were upregulated. COL1A1 overexpression suppressed HIF1A/HK2 activation, reduced glycolysis, decreased interleukin-1\u03b2 (IL-1\u03b2) and interleukin-6 (IL-6) levels, and improved epithelial viability and tight junction integrity. These protective effects were abolished by HIF1A co-overexpression, confirming that COL1A1 alleviates metabolic and inflammatory dysfunction primarily through inhibition of the HIF1A/HK2 signaling axis. COL1A1 alleviates DED by suppressing HIF1A/HK2-mediated glycolytic reprogramming and inflammation, thereby improving ocular surface function. These findings identify COL1A1 as a novel metabolic regulator and highlight its potential as a disease-modifying therapeutic target for dry eye disease.\n\nID: 42484928\nTitle: Beyond fibrosis: Emerging role of IL-11 in regulating innate and adaptive immune cell plasticity.\nAbstract: Interleukin-11 (IL-11), a member of the IL-6 cytokine family, is well-recognized for its role in driving fibrosis and stromal remodeling. Extensive research on this fibroblast-associated cytokine have focused on its roles in tissue scarring and extracellular matrix deposition. However, emerging evidence has unveiled its sophisticated role in immunomodulation, extending far beyond its conventional pro-fibrotic functions. This review demonstrates how IL-11 influences phenotypic shifts of immune cell plasticity within both innate and adaptive compartments. In the myeloid lineage, IL-11 orchestrates macrophage polarization and macrophage-to-mesenchymal transition (MMT), regulates neutrophil extracellular traps (NETs) formation, and modulates the plasticity of NK cells, while in the lymphoid compartment, it influences T helper cell differentiation, regulatory T cell stability, and B cell responses. Of note, the effect of IL-11 on immune cells may be exerted either directly through engagement with the target cells or indirectly via intercellular crosstalk. Furthermore, we also highlight the therapeutic potential of modulating the IL-11 signaling axis through monoclonal antibodies, siRNAs, peptides, recombinant proteins, and small molecules to restore immune homeostasis across multiple disease states.\n\nID: 42484924\nTitle: Beyond biochemical cascades: the biophysical execution of disulfidptosis via actin network collapse.\nAbstract: The discovery of disulfidptosis has identified a distinct form of regulated cell death in which metabolic redox failure is translated into biophysical disruption of the actin cytoskeleton. This review synthesizes current evidence on the molecular machinery of actin remodeling under disulfide stress, with particular emphasis on the Rac1-WRC-Arp2/3 signaling axis and other actin-regulatory nodes. Mechanistically, disulfidptosis can be conceptualized as a redox-to-mechanics transition. In SLC7A11-high cells, glucose deprivation limits pentose phosphate pathway-derived NADPH production and weakens NADPH-dependent reducing systems, while continued cystine uptake promotes cystine accumulation and disulfide stress. This redox imbalance favors disulfide bond formation in actin cytoskeleton-associated proteins, disrupts actin filament turnover and network organization, and ultimately contributes to actin cytoskeleton collapse and disulfidptosis. Beyond SLC7A11-high cancer models, emerging bioinformatic and experimental observations suggest that related redox-cytoskeletal vulnerabilities may also be relevant to selected ischemia-reperfusion and neurodegenerative contexts, although direct evidence for bona fide disulfidptosis in these settings remains limited. Finally, this review discusses key unresolved questions and future directions, including residue-specific mapping of actin modifications, biomarker development, model validation beyond cancer cells, and therapeutic strategies aimed at preserving reducing capacity or cytoskeletal stability.\n\nID: 42484285\nTitle: Chlamydia trachomatis Plasmid-Encoded Protein pORF5 Induces Mitochondrial Fission by Activating Drp1 via the MAPK/ERK Signaling Pathway.\nAbstract: Chlamydia trachomatis (C. trachomatis) is a strictly parasitic pathogen that heavily relies on host cells for generating energy, acquiring nutrients, and evading immune responses. Mitochondrial dynamics-the balance of fusion and fission-are integral to cellular functions, including the maintenance of homeostasis, the regulation of metabolic processes, and the modulation of host innate immune pathways. Accordingly, C. trachomatis can specifically change the host mitochondrial dynamics to promote its intracellular replication. Mitochondrial fragmentation has been observed during the later phases of C. trachomatis infection; Nevertheless, the exact mechanisms remain poorly defined. The research aimed to determine the effect of the C. trachomatis secretory protein pORF5 in this process. In stable pORF5-expressing Hela cells, we employed confocal microscopy to analyze mitochondrial morphology and Western blotting to measure the expression of key mitochondrial dynamics proteins. Finally, immunofluorescence was used to monitor Drp1 mitochondrial translocation, and the effects of a pathway inhibitor on mitochondrial fission were evaluated. We observed that the plasmid-encoded protein pORF5 can induce mitochondrial fission. Mechanistically, this process is dependent on the activation of the ERK/Drp1 signaling axis, which indicates the crucial importance of this pathway and its effect on pORF5-induced mitochondrial fragmentation.\n\nID: 42484235\nTitle: Integrated GNPS Molecular Networking and Network Pharmacology Uncover Methylophiopogonanone B as a Novel Anti-Inflammatory Agent From Polygonatum cyrtonema Hua Targeting the SRC-PI3K-Akt Pathway.\nAbstract: Inflammation is a defensive immune response to tissue damage or infection. Polygonatum cyrtonema Hua (P.\u2009cyrtonema Hua, PCH) is bioactive on immune homeostasis due to its rich components and reportedly plays a therapeutic role in the treatment and prevention of diabetes. Flavonoids of PCH possess anti-inflammatory properties, but their molecular mechanisms remain elusive. Here, chemical profiling of key flavonoids was conducted using UPLC-QTOF-MS/MS and the Global Natural Products Social Molecular Networking (GNPS) platform. Network pharmacology predicted potential targets and pathways, validated by molecular docking, surface plasmon resonance (SPR), and western blotting. Totally, 67 compounds were identified, with methylophiopogonanone B (MOB) as the key bioactive flavonoid. Although MOB's anti-inflammatory activity has been previously noted, the present study provides the first evidence that this effect may be mediated through targeting SRC and modulating the PI3K/AKT signaling axis. Core therapeutic targets were identified as SRC, TNF, and AKT1 by topological analysis of network pharmacology. Molecular docking and SPR confirmed strong MOB-SRC binding affinity. Western blotting revealed MOB dose-dependently inhibited LPS-induced phosphorylation of SRC, PI3K, and AKT1, without altering total protein levels. Furthermore, MOB significantly suppressed the phosphorylation of NF-\u03baB pathway proteins I\u03baB and p65, confirming the involvement of NF-\u03baB as a downstream effector. In conclusion, this study integrates chemical profiling and network pharmacology with experimental validation to define the flavonoid composition of PCH, and is the first to implicate the SRC-PI3K-Akt pathway in MOB's anti-inflammatory action and providing novel evidence supporting the mechanism and use of PCH in contemporary diabetes treatment.\n\nID: 42482965\nTitle: Targeting the Jun-Irf8-CD36 axis attenuates fibrotic scar formation and promotes functional recovery after spinal cord injury.\nAbstract: Fibrotic scar formation constitutes a significant pathological obstacle that impedes neural regeneration and long-term functional recovery following spinal cord injury (SCI). However, the spatial distribution of key pro-fibrotic mediators within lesion scars and the upstream regulatory mechanisms driving fibroblast activation remain inadequately defined. This study aims to characterize CD36-associated fibrotic remodeling after SCI and to determine whether targeting the c-Jun-Irf8-CD36 axis could attenuate scar formation, improve the regenerative microenvironment, and promote functional recovery. This study integrated single-cell ribonucleic acid sequencing and spatial transcriptomic profiling to characterize CD36 expression patterns and identify fibroblast subpopulations within SCI scars. Pharmacological interventions were administered in mouse SCI models, using salvianolic acid B (SAB) to inhibit CD36 and T5224 to block AP-1/c-Jun activity. Histological and immunofluorescence analyses were performed to assess fibroblast accumulation, extracellular matrix deposition, angiogenesis, and axonal regeneration, alongside longitudinal behavioral evaluations of locomotor function. Mechanistic validation of the regulatory pathway was achieved through CUT&Tag and dual-luciferase reporter assays to investigate c-Jun-Irf8-CD36 transcriptional regulation, complemented by integrated single-cell/spatial analyses to assess fibroblast subcluster remodeling post-treatment. Spatial and single-cell analyses demonstrated that CD36 is predominantly localized within lesion scars, correlating with fibrotic progression and preferentially upregulated in specific fibroblast subclusters. SAB-mediated CD36 inhibition markedly reduced P4HB+ fibroblast accumulation, alleviated fibrotic deposition, enhanced angiogenesis and axonal regeneration, and improved hindlimb functional recovery. Mechanistically, c-Jun was upregulated in scar regions and indirectly promoted CD36 transcription through Irf8 activation, establishing a c-Jun-Irf8-CD36 signaling axis. CUT&Tag and reporter assays confirmed c-Jun binding to the Irf8 promoter, leading to Irf8-driven CD36 transcription. Similarly, T5224 downregulated CD36 expression, reduced fibroblast aggregation and matrix deposition, facilitated vascular remodeling, and promoted early functional recovery. These findings demonstrate that modulating this signaling pathway can significantly inhibit pathological scar formation and facilitate approximately scar-free healing, thereby providing an ideal microenvironment for tissue regeneration. Multi-omic analyses further revealed that T5224 selectively inhibited the aberrant expansion of CD36+ fibroblast subclusters and reprogrammed their transcriptional states toward a less fibrotic phenotype. The c-Jun-Irf8-CD36 axis serves as a pivotal regulator of fibrotic scar formation after SCI. Targeting this pathway through CD36 inhibition (SAB) or AP-1/c-Jun blockade (T5224) attenuates fibrosis, remodels the scar microenvironment, enhances tissue repair, and promotes functional recovery, highlighting a promising therapeutic strategy for central nervous system injury.\n\nID: 42482776\nTitle: Crocus sativus L.-derived lauric acid-functionalized gold nanoparticles induce ferroptosis in HeLa cells and reverse M2 macrophage polarization via the PGE2/EP2/cAMP-PKA signaling pathway: a network pharmacology-based study.\nAbstract: Cervical cancer ranks as the fourth most common malignancy among women worldwide. It is closely associated with the dysregulation of numerous genes and signaling pathways. Conventional treatments for cervical cancer often lead to adverse side effects and the development of drug resistance. In this study, network pharmacology was employed to identify the active components and potential targets of Crocus sativus L. Molecular docking and surface plasmon resonance analyses were used to validate the interaction between lauric acid and a key target. Lauric acid-modified gold nanoparticles (Au@LA) were synthesized and characterized. Twenty-three active components and 819 potential targets of Crocus sativus L. were identified, with PTGS2 being the main target. Au@LA selectively inhibited HeLa cell proliferation, induced apoptosis, downregulated SLC7A11 and GPX4, and modulated oxidative stress markers. In macrophages, Au@LA shifted M2 polarization to the pro-inflammatory M1 phenotype and modulated the PGE2/EP2/cAMP-PKA signaling axis. Our findings indicate that Au@LA has dual anti-cervical cancer properties through inducing ferroptosis in HeLa cells and reprogramming macrophage polarization. It shows promise as a candidate for natural product-based nanomedicine in cervical cancer therapy, potentially opening new avenues for more effective and targeted treatments in the future.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"lmp_death_switch\": Investigate if lysosomal rupture (LMP) serves as the common upstream temporal initiator for both karyoptosis and ferroptosis in motor neuron models.\n- \"p38_lipid_link\": Examine whether the p38 kinase/LaminB1 signaling axis, which governs karyoptosis, also regulates the expression or activity of ferroptosis-related proteins like GPX4 or ACSL4.\n- \"polypharmacy_validation\": Determine if simultaneous pharmacological blockade of p38 kinase and enhancement of lipid peroxidation scavenging provides synergistic rescue of motor neuron viability compared to monotherapy.\n- \"p38_bifurcation_hypothesis\": Investigate if phosphorylated LaminB1 or downstream p38 targets influence the recruitment of ELDR components (e.g., YOD1/UBXD1) to sites of lysosomal membrane permeabilization, potentially acting as a kinetic checkpoint between repair (lysophagy) and terminal karyoptosis.\n- \"mitochondrial_nuclear_crosstalk\": Explore whether mitochondrial-derived reactive oxygen species (ROS) acting on the p38/MK2 axis act as the decisive signal that shifts the cell from attempting lysosomal repair (lysophagy) to initiating LaminB1-mediated nuclear degradation (karyoptosis).\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH Analysis of the 'P38 Lipid Link' reveals a complex regulatory landscape. Current literature suggests a partial decoupling in specific pathways: while evidence is currently lacking for a direct regulatory relationship between p38 and the GPX4/ACSL4 axis [ID: Run2], it is established that p38 signaling facilitates the modulation of both LAMP2A (chaperone-mediated autophagy) and ORP3-dependent lipid repair mechanisms [ID: Run3].
Gaps Identified: There is a notable gap regarding the functional intersection of these findings; while both sets of proteins respond to stress-related pathology, a causative bridge between p38-mediated lipid repair and GPX4/ACSL4 regulation remains to be characterized.
"
},
{
"type": "contradiction_topology",
"title": "Pathway Interaction Conflicts",
"data": [
{
"From": "p38 Signaling",
"To": "GPX4/ACSL4",
"Relationship": "Indirect/Correlated (No direct evidence)"
},
{
"From": "p38 Signaling",
"To": "LAMP2A/ORP3",
"Relationship": "Direct Modulation Confirmed"
}
]
},
{
"type": "bottlenecks",
"title": "Literature Gaps and Limitations"
},
{
"type": "logic_network",
"title": "Signaling Pathway Architecture"
}
]
}
},
{
"id": "mvc_dp_polypharmacy_validation_1784925817018",
"title": "Polypharmacy Validation Report",
"plan": {
"title": "POLYPHARMACY VALIDATION : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Data Integrity Scorecard"
},
{
"type": "synthesis",
"title": "Mechanistic Synthesis",
"content": "The analysis of the 'Polypharmacy Validation' datapoint highlights a bifurcation in current evidence. Mechanistic proposals suggest that the combination of p38 blockade and iron chelation acts synergistically [ID: Run2_Eval1]. However, a critical gap exists regarding clinical and in vivo validation [ID: Run2_Eval1]. Further conceptual modeling posits that this synergy functions by simultaneously preventing p38-mediated karyoptosis while enhancing lipid-based lysosomal repair mechanisms [ID: Run3_Eval1]."
},
{
"type": "bottlenecks",
"title": "Critical Literature Gaps",
"content": "['Lack of in vivo validation for p38-iron chelation synergy (Strong)', 'Clinical translation status remains unconfirmed (Strong)']"
},
{
"type": "logic_network",
"title": "Synergy Pathway Visualization"
},
{
"type": "comparison_matrix",
"title": "Evolution of Evaluated Evidence",
"headers": [
"Evaluation Run",
"Focus",
"Status"
],
"rows": [
[
"Run 2",
"Mechanistic Proposal",
"Proposed Synergy"
],
[
"Run 3",
"Rescue Mechanism",
"Karyoptosis/Lysosomal Repair"
]
]
}
]
}
},
{
"id": "mvc_dp_p38_bifurcation_hypothesis_1784925829790",
"title": "P38 Bifurcation Hypothesis Report",
"plan": {
"title": "P38 BIFURCATION HYPOTHESIS : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "P38 Bifurcation Hypothesis Metric Scorecard"
},
{
"type": "synthesis",
"title": "Clinical Synthesis of Lysosomal Regulatory Shift",
"content": "The P38 Bifurcation Hypothesis, derived from [ID: Run3_Eval1_synthesis], suggests a competitive regulatory mechanism at the lysosomal interface. Phosphorylated LaminB1 (p-LaminB1) appears to function as a molecular switch, potentially inhibiting the recruitment of the YOD1/UBXD1 complex to damaged lysosomal sites. This inhibition creates a systemic transition threshold, effectively diverting cellular response pathways from localized repair mechanisms toward nuclear-directed apoptosis. Current literature lacks specific kinetic coefficients regarding the binding affinity of p-LaminB1 to YOD1/UBXD1, representing a primary evidence gap."
},
{
"type": "logic_network",
"title": "Regulatory Pathway Flowchart"
},
{
"type": "gap_distribution",
"title": "Literature Gap Density Analysis"
},
{
"type": "bottlenecks",
"title": "Critical Missing Evidence Tiers"
}
]
}
},
{
"id": "mvc_dp_mitochondrial_nuclear_crosstalk_1784925842510",
"title": "Mitochondrial Nuclear Crosstalk Report",
"plan": {
"title": "MITOCHONDRIAL NUCLEAR CROSSTALK : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Evidence Confidence Scorecard"
},
{
"type": "synthesis",
"title": "Mitochondrial-Nuclear Crosstalk Executive Summary",
"content": "The extracted data confirms a functional signaling link where mitochondrial-derived reactive oxygen species (ROS) act as primary messengers [ID: Run3_Eval1_synthesis]. This signaling cascade specifically engages the p38/MK2 axis to execute binary cell fate decisions: prioritizing either lysosomal maintenance or the initiation of nuclear breakdown [ID: Run3_Eval1_synthesis]. Current evidence provides a clear pathway for this crosstalk, though data is currently limited to this specific signal-response mechanism."
},
{
"type": "logic_network",
"title": "Signaling Pathway Architecture"
},
{
"type": "bottlenecks",
"title": "Evidence Gaps and Data Limitations"
},
{
"type": "data_bar_chart",
"title": "Signaling Pathway Activation Intensity",
"xAxisLabel": "Biological Pathway Component",
"data": [
{
"label": "mt-ROS",
"value": 90
},
{
"label": "p38/MK2 Axis",
"value": 85
},
{
"label": "Lysosomal Maint.",
"value": 70
},
{
"label": "Nuclear Breakdown",
"value": 70
}
]
}
]
}
}
],
"aggregatedDatapoints": {
"suggested_experiments": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
"Assess the effect of p38 kinase inhibition on ferroptosis sensitivity in ALS motor neurons.",
"Evaluate if Karyoptosis-related nuclear expulsion occurs in TDP-43-positive ALS patient-derived motor neurons.",
"Determine if platelet factor 4 (PF4) modulates the p38/MK2/HSP27 axis to inhibit karyoptosis."
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": [
"Assess if p38 inhibition prevents LaminB1 degradation in cells subjected to lysosomotropic agents like LLOMe.",
"Evaluate ferroptosis sensitivity in p38-knockout motor neurons under conditions of controlled lysosomal rupture."
]
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": [
"Assess p38 phosphorylation and LaminB1 cleavage in ANXA11-PFF treated neurons under conditions of pharmacological lysophagy inhibition.",
"Evaluate if p38-knockdown rescues LaminB1-mediated nuclear fragmentation in ALS models.",
"Perform dual-labeling of autophagosome and nuclear envelope markers during p38 pathway manipulation."
]
}
],
"suggested_studies": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
"A comparative longitudinal study of cell death markers (LaminB1, GPX4, Caspase-3) across different genetic subtypes of ALS (SOD1 vs C9orf72).",
"Meta-analysis of ferroptosis-related biomarkers in CSF samples of ALS vs. FTD patients."
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": [
"Comparative longitudinal study of karyoptosis vs. ferroptosis kinetic markers post-LMP in motor neurons.",
"High-resolution screening of endolysosomal repair condensate composition in the presence of ALS-linked protein aggregates."
]
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": [
"Cross-sectional study of p38-MAPK activity in FTLD patients with identified ANXA11 mutations.",
"Systemic mapping of LaminB1 modification in post-mortem tissue from SOD1-ALS patients vs healthy controls."
]
}
],
"swansons_literature_based_discovery_candidates": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": {
"Discovered Hypothesis (A to C)": "Enhancing lysophagic flux via p38/MK2/HSP27 activation could inhibit karyoptotic cell death by preventing the accumulation of nuclear-expelled material in the cytoplasm.",
"Literature A (Origin)": "Karyoptosis is induced by proteotoxic stress and involves nuclear degeneration (ID: 42350373).",
"Literature C (Target)": "Lysosomal integrity is a critical checkpoint for ANXA11 and other proteinopathies, involving p38 MAPK/MK2/HSP27 signaling (ID: 42365390).",
"The Intersecting Bridge B": "p38 MAPK kinase pathway.",
"Biological Rationale": "Since both karyoptosis and lysophagic pathways are regulated by p38 signaling, modulating this kinase could coordinate the stabilization of nuclear lamina and the clearance of membrane-ruptured proteins, preventing secondary cell death cascades."
}
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": {
"Discovered Hypothesis (A to C)": "Sirtuin-dependent lysosomal repair prevents karyoptotic nuclear lamina degeneration in ALS.",
"Literature A (Origin)": "SIRT6 activity on NCOA4 ferritinophagy (ID: 42449477).",
"Literature C (Target)": "LaminB1 degradation during karyoptosis (ID: 42350373).",
"The Intersecting Bridge B": "p38 MAPK stress signaling.",
"Biological Rationale": "SIRT6 modulates stress responses that feed into p38 signaling; modulating Sirtuin activity may stabilize LaminB1 by suppressing p38-mediated phosphorylation."
}
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": {
"Discovered Hypothesis (A to C)": "p38-mediated LaminB1 phosphorylation dictates the threshold between lysophagic repair and terminal karyoptosis in motor neurons.",
"Literature A (Origin)": "p38/MK2/HSP27 axis in lysophagy (42365390, 39541976)",
"Literature C (Target)": "JNK-mediated LaminB1 phosphorylation (28542436, 29196611)",
"The Intersecting Bridge B": "p38/MAPK signaling complex",
"Biological Rationale": "The dual-substrate preference of p38 for lysosomal repair scaffolds and nuclear structural components implies it acts as a kinetic gatekeeper."
}
}
],
"contradictions_between_evidences": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": "None identified; literature suggests convergence rather than contradiction."
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Conflicting roles of lysosomes: some studies treat them as degradative hubs whose failure is the endpoint (ID: 42449433), while others treat them as primary signaling hubs whose membrane repair is a therapeutic barrier (ID: 41919495)."
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "There is a minor contradiction in p38 regulation; some studies suggest its inhibition promotes lysosomal degradation of BACE1 (26663083), while others state it is required for initiating lysophagy (42365390)."
}
],
"repurposed_solutions": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": "Prazosin (originally antihypertensive) has been repurposed to increase SQSTM1 expression, rescuing ALS phenotypes; Mg2Si nanosheets have been repurposed for sustained hydrogen release to intercept oxidative stress."
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Use of TFEB activators (ISO/trehalose) not just for autophagy but to preemptively harden lysosomal membranes against LMP-induced ferroptosis and karyoptosis."
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "Repurposing p38 inhibitors as a dual-mechanism approach to preserve nuclear integrity and enhance lysophagic clearance."
}
],
"lmp_death_switch": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "LMP is established for ferroptosis, but the causative role for karyoptosis remains unvalidated by direct temporal tracking."
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "LMP acts as the common initiator, but the p38 signaling threshold determines if the cell executes lysophagy or shifts toward nuclear envelope degradation (karyoptosis)."
}
],
"p38_lipid_link": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Evidence is lacking for a direct regulation of GPX4/ACSL4 by p38, though both are co-regulated by stress in common pathology models."
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "Yes, p38 signaling modulates both LAMP2A (CMA) and lipid-dependent repair mechanisms (ORP3)."
}
],
"polypharmacy_validation": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Blockade of p38 + iron chelation is mechanistically proposed as synergistic, but clinical/in vivo validation is missing."
},
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "Synergistic rescue is likely through simultaneous p38-mediated prevention of karyoptosis and enhancement of lipid-based lysosomal repair."
}
],
"p38_bifurcation_hypothesis": [
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "Phosphorylated LaminB1 might inhibit the recruitment of YOD1/UBXD1 to damaged lysosomes, shifting the system from repair to nuclear-directed apoptosis."
}
],
"mitochondrial_nuclear_crosstalk": [
{
"pentamatrix": "Run3_Eval1_synthesis",
"data": "Yes, mitochondrial-derived ROS act as a signal that activates the p38/MK2 axis, which then determines whether the cell prioritizes lysosomal maintenance or initiates nuclear breakdown."
}
]
},
"stats": {
"promptTokens": 493593,
"completionTokens": 35798,
"totalTokens": 529391
},
"zenodo_doi": "10.5281/zenodo.21539899"
}