ID: 29388501
Title: Karyoptosis: A novel type of cell death caused by chronic autophagy inhibition.
Abstract: Macroautophagy/autophagy influences onset and progression of several human neurodegenerative diseases, because of its critical role as a regulator of neuronal proteostasis and organelle quality control. In many neurodegenerative diseases, impairment in autophagy is thought to play a fundamental part in the terminal phases of cellular degeneration and death. However, the ultimate mechanism of neuronal cell death remains elusive. In a recent study we have identified a new form of regulated cell death, which arises upon autophagy inhibition.

ID: 30631036
Title: Lamin B is a target for selective nuclear PQC by BAG3: implication for nuclear envelopathies.
Abstract: Nuclear envelopathies are recognized genetic disorders affecting individuals with mutations in their genes encoding members of the lamin family of nuclear envelope proteins that are responsible for maintaining the architectural structure of the nucleus. Irregularity in shape and size of the nuclei, nuclear membrane rupture, and appearance of micronuclei in the cytoplasm are among the pathological features of the syndrome. Here, we demonstrate that Bcl2-associated anthanogene-3 (BAG3), a stress-induced co-chaperone protein that by association with heat-shock protein 70 (HSP70) participates in regulation of autophagy, plays a critical role in the integrity of the nuclear membrane in cardiomyocytes. Cells subjected to proteotoxic stress or BAG3 downregulation show perinuclear accumulation of the aberrant ubiquitinated proteins that are often associated with the appearance of misshapen, enlarged, and elongated nuclei. There were dense accumulations of lamin B in the perinuclear area and distribution of lamin B-positive micronuclei in the cytoplasmic space, indicative of nuclear envelope rupture. Overexpression of BAG3 in cells under proteotoxic stress ameliorated pathological nuclear morphology and reduced cytoplasmic distribution of the micronuclei particles. Subcellular co-localization and co-immunoprecipitation demonstrated interaction of lamin B with the BAG domain of BAG3 and HSP70, suggesting the importance of BAG3 in the selective clearance of a surplus of aggregated lamin B that is generated during stress conditions. Our findings define a novel role for BAG3 in nuclear protein quality control and suggest an alternative pathogenetic pathway that contributes to the development of nuclear envelopathies.

ID: 32788068
Title: ROS/p38MAPK-induced lamin B1 accumulation promotes chronic kidney disease-associated vascular smooth muscle cells senescence.
Abstract: The incidence of cardiovascular thrombotic events which are highly associated with atherosclerotic plaque vulnerability and its rupture is much higher in chronic kidney disease (CKD) patients than that in the general population. It has been reported that the thinning of fibrous cap in atherosclerotic plaque is a crucial factor in plaque vulnerability and thrombosis. Moreover, vascular smooth muscle cells (VSMCs) senescence play a crucial role in maintaining the thickness of fibrous cap. Lamin B1, one of the members of laminin family, is an important component of the nuclear membrane and it is related to cell senescence. While whether lamin B1 participates CKD-related VSMCs senescence and plaque vulnerability and the underlying mechanism remain unclear. Here, we found that CKD promoted fibrous cap thinning and reduced the stability of atherosclerotic plaque through accelerating VSMCs senescence. VSMCs senescence induced by CKD was related to the increased expression of lamin B1 and abnormality of nuclear membrane structure. Knocking down the expression of lamin B1 with RNA interference prevented CKD-induced aberrant nuclear membrane structure and senescence in VSMCs. Additionally, overproduction of reactive oxidative stress (ROS) and subsequent activation of ROS/p38MAPK under CKD milieus contribute to these series of outcomes, as scavenging ROS with N-acety-l-cysteine (NAC) or inhibiting p38MAPK signal pathway with SB203580 could inhibit CKD-induced activation of ROS/p38MAPK, increased expression of lamin B1, abnormality of nuclear membrane structure and VSMCs senescence. Taken together, these results suggested that ROS/p38MAPK-mediated increased expression of lamin B1 and abnormality of nuclear membrane structure was an important mechanism of CKD-induced VSMCs senescence.

ID: 34290138
Title: Nuclear envelope budding is a response to cellular stress.
Abstract: Nuclear envelope budding (NEB) is a recently discovered alternative pathway for nucleocytoplasmic communication distinct from the movement of material through the nuclear pore complex. Through quantitative electron microscopy and tomography, we demonstrate how NEB is evolutionarily conserved from early protists to human cells. In the yeast Saccharomyces cerevisiae, NEB events occur with higher frequency during heat shock, upon exposure to arsenite or hydrogen peroxide, and when the proteasome is inhibited. Yeast cells treated with azetidine-2-carboxylic acid, a proline analog that induces protein misfolding, display the most dramatic increase in NEB, suggesting a causal link to protein quality control. This link was further supported by both localization of ubiquitin and Hsp104 to protein aggregates and NEB events, and the evolution of these structures during heat shock. We hypothesize that NEB is part of normal cellular physiology in a vast range of species and that in S. cerevisiae NEB comprises a stress response aiding the transport of protein aggregates across the nuclear envelope.

ID: 37998344
Title: mTOR Inhibitor Rapalink-1 Prevents Ethanol-Induced Senescence in Endothelial Cells.
Abstract: The cardiovascular risk factors, including smoking, ethanol, and oxidative stress, can induce cellular senescence. The senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase (MMPs). These pro-inflammatory molecules and MMPs promote the infiltration and accumulation of inflammatory cells in the vascular tissue, exacerbating vascular tissue inflammation. MMPs damage vascular tissue by degenerating the extracellular matrix. Consequently, these cellular and molecular events promote the initiation and progression of cardiovascular diseases. We used Rapalink-1, an mTOR inhibitor, to block ethanol-induced senescence. Rapalink-1 inhibited oxidative-stress-induced DNA damage and senescence in endothelial cells exposed to ethanol. It attenuated the relative protein expression of senescence marker P21 and improved the relative protein expression of DNA repair protein KU70 and aging marker Lamin B1. It inhibited the activation of NF-κB, MAPKs (P38 and ERK), and mTOR pathway proteins (mTOR, 4EBP-1, and S6). Moreover, Rapalink-1 suppressed ethanol-induced mRNA expression of ICAM-1, E-selectin, MCP-1, IL-8, MMP-2, and TIMP-2. Rapalink-1 also reduced the relative protein expression of MMP-2. In summary, Rapalink-1 prevented senescence, inhibited pro-inflammatory pathway activation, and ameliorated pro-inflammatory molecule expression and MMP-2.

ID: 38570838
Title: Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation.
Abstract: Smoking is the major cause of cardiovascular diseases and cancer. It induces oxidative stress, leading to DNA damage and cellular senescence. Senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase, which are known to play a vital role in the initiation and progression of cardiovascular diseases and metastasis in cancer. The current study investigated the smoking induced cellular senescence and employed colchicine that blocked senescence in endothelial cells exposed to tobacco smoke condensate. Colchicine prevented oxidative stress and DNA damage in tobacco smoke-condensate-treated endothelial cells. Colchicin reduced β-gal activity, improved Lamin B1, and attenuated cell growth arrest markers P21 and P53. Colchicine also ameliorated the expression of SASP factors and inhibited the activation of NF-kB and MAPKs P38 and ERK. In summary, colchicine inhibited tobacco smoke condensate-induced senescence in endothelial cells by blocking the activation of NF-kB and MAPKs P38 and ERK.

ID: 39625813
Title: Karyoptosis as a novel type of UVB-induced regulated cell death.
Abstract: Karyoptosis is a type of regulated cell death (RCD) characterized by explosive nuclear rupture caused by a loss of nuclear membrane integrity, resulting in the release of genomic DNA and other nuclear components into the cytosol and extracellular environment. The mechanism underlying karyoptosis involves a delicate balance between the following forces: the expansion force exerted by the tightly packed DNA in the nucleus, the resistance provided by the nuclear lamina at the inner nuclear membrane (INM), and the tensile force from the cytoskeleton that helps position the nucleus at the center of the cytoplasm, allowing it to remain maximally expanded. In addition, CREB3, a type II integral membrane protein with DNA-binding ability, tethers chromatin to the INM, providing a tightening force through chromatin interactions that prevent nuclear membrane rupture. UVB radiation can trigger this process, inducing CREB3-FL cleavage and producing CREB3-CF. Therefore, UVB acts as an intrinsic factor in the induction of karyoptosis. Importantly, biochemical analysis of RCD markers shows that karyoptosis is distinct from other forms of cell death, such as apoptosis, autophagy, necroptosis, and pyroptosis. This review explores the mechanisms involved in maintaining nuclear membrane integrity and the role of CREB3 in triggering karyoptosis and provides brief suggestions on the potential implications for targeting cancer cells.

ID: 39908177
Title: Neuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy.
Abstract: Multiple system atrophy (MSA) is a rare, rapidly progressing neurodegenerative disorder often misdiagnosed as Parkinson's disease (PD). Although both conditions share some clinical features, MSA is distinct in its pathological hallmark: oligodendroglial cytoplasmic α-synuclein (α-Syn) inclusions, known as glial cytoplasmic inclusions. These glial cytoplasmic inclusions are pathognomonic for MSA, but they do not lead to significant oligodendroglial cell loss. Instead, MSA is characterized by a substantially greater loss of non-dopaminergic neurons in the nigrostriatal and olivopontocerebellar systems compared with PD. This widespread neuronal degeneration, which is not seen to the same extent in PD, plays a crucial role in the clinical presentation of MSA and is important to consider if PD is to be redefined as a neuronal α-Syn disease. It also raises the question of differences in the potential toxicity of lesions in MSA and the underlying cause of neuronal death in MSA. By combining an N-terminus α-Syn antibody that reveals more α-Syn pathology and super-resolution microscopy, we identified α-Syn fibrils in MSA neurons penetrating the nucleus from the cytoplasm, leading to nuclear destruction and neuronal death. Our data indicate an early invasion of neuronal nuclei by α-Syn pathology in MSA, precipitating rapid nuclear envelope destruction, as observed through significant structural damage, including the loss of Lamin integrity. Although the progression of α-Syn pathology from the cytoplasm to the nucleus might be similar in oligodendroglia and neurons, the aggregation state of the α-Syn proteoforms involved differs because proteolytic resistance of α-Syn inclusions is significantly higher in neurons, and the nucleus is destroyed. We describe the progressive impact of α-Syn nuclear pathology on MSA neurons and show that this is a more detrimental and rapid pathology driving neurodegeneration. Our data suggest that oligodendroglial inclusions contain more soluble, less toxic α-Syn proteoforms, consistent with two distinct α-Syn filaments in MSA. We propose renaming MSA as a neuronal nuclear and oligodendroglial α-synucleinopathy to reflect these two distinct pathologies better.

ID: 40339618
Title: Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology.
Abstract: Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions.

ID: 40475464
Title: Tau Oligomerization Drives Neurodegeneration via Nuclear Membrane Invagination and Lamin B Receptor Binding in Alzheimer's disease.
Abstract: The microtubule-associated protein tau aggregates into oligomeric complexes that highly correlate with Alzheimer's disease (AD) progression. Increasing evidence suggests that nuclear membrane disruption occurs in AD and related tauopathies, but whether this is a cause or consequence of neurodegeneration remains unclear. Using the optogenetically inducible 4R1N Tau::mCherry::Cry2Olig (optoTau) system in iPSC-derived neurons, we demonstrate that tau oligomerization triggers nuclear rupture and nuclear membrane invagination. Pathological tau accumulates at sites of invagination, inducing structural abnormalities in the nuclear envelope and piercing into the nuclear space. These findings were confirmed in the humanized P301S tau (PS19) transgenic mouse model, where nuclear envelope disruption appeared as an early-onset event preceding neurodegeneration. Further validation in post-mortem AD brain tissues revealed nuclear lamina disruption correlating with pathological tau emergence in early-stage patients. Notably, electron microscopy shows that tau-induced nuclear invagination triggers global chromatin reorganization, potentially driving aberrant gene expression and protein translation associated with AD. These findings suggest that nuclear membrane disruption is an early and possibly causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization and nuclear stress. Further investigation into nuclear destabilization could inform clinical strategies for mitigating AD pathogenesis.

ID: 41169507
Title: Endolysosomal dysfunction impairs proteostasis and induces neurodegeneration in vivo.
Abstract: Transactive response (TAR) DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. Dysfunction of the endolysosomal system, which plays a crucial role in protein trafficking and maintaining proteostasis, has been implicated in FTD-ALS pathogenesis. While the impact of endolysosomal dysfunction on TDP-43 pathology remains unclear, we demonstrated that disrupting the endolysosomal pathway by expressing the constitutively active endosomal protein, Rab5Q79L, induces TDP-43 aggregation in cultured cells. Here, we generated a mouse model expressing GFP-tagged Rab5Q79L, demonstrating that GFP-Rab5Q79L mice exhibit early motor deficits and endolysosomal dysfunction, including enlarged endosomes, abnormal lysosome morphology, and p62- or ubiquitin-positive inclusions. These mice also developed significant neuronal loss, neuroinflammation, phosphorylated TDP-43 (pTDP-43) inclusions, and nuclear envelope and nuclear pore structural defects reminiscent of FTD-ALS. Accordingly, GFP-Rab5Q79L mice will prove useful in expanding our understanding of endolysosomal dysfunction in proteostasis and pTDP-43 pathology.

ID: 41303380
Title: New Roles of bZIP-Containing Membrane-Bound Transcription Factors in Chromatin Tethering and Karyoptosis.
Abstract: The nuclear membrane has emerged as a dynamic regulatory platform coordinating genome organization, mechanotransduction, and regulated cell death (RCD). Beyond its barrier function, the nuclear skeleton-comprising lamins, actin-myosin isoforms, nuclear matrix proteins, and the LINC complex-supports nuclear integrity and gene regulation. Recent evidence shows that type II membrane-bound bZIP transcription factors such as cAMP-responsive element-binding protein 3 (CREB3) and CREB3L1 localize to the inner nuclear membrane (INM), linking chromatin tethering with stress signaling. Their stress-induced cleavage by S1P/S2P disrupts chromatin anchoring and, in some contexts, triggers karyoptosis, a novel form of RCD defined by nuclear rupture. These findings position the nuclear envelope (NE) as a mechanosensitive signaling hub with direct implications for disease and therapy. In this review, we provide a comprehensive discussion on how type II membrane-bound bZIP transcription factors and chromatin acting as a nucleoskeleton cooperate to regulate nuclear membrane integrity.

ID: 41544689
Title: Regulated cell death in COPD: Modulators, crosstalk mechanisms, and therapeutic opportunities.
Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disorder, with emerging evidence highlighting the central role of regulated cell death (RCD) in its pathogenesis. However, the regulatory mechanisms, crosstalk between different RCD pathways, and their role in intercellular communication remain poorly understood. This review examines major forms of RCD (apoptosis, necroptosis, ferroptosis, pyroptosis, NETosis, and PANoptosis) in COPD, exploring their regulation, crosstalk, role in intercellular signaling, and potential as therapeutic targets. Mechanistically, RCD is regulated through membrane receptors, epigenetic modifications, and post-translational processes. Endoplasmic reticulum (ER) stress, reactive oxygen species, and autophagy serve as common nodes across multiple RCD types. Excessive ER stress triggers apoptosis, while impaired autophagy promotes oxidative stress, cellular senescence, and inflammation. Conversely, excessive autophagy-including mitophagy, ferritinophagy, lysosomal autophagy, ER-phagy, and chaperone-mediated autophagy-can induce apoptosis, necroptosis, and ferroptosis. Regarding inter-pathway crosstalk and RCD-mediated intercellular communication: reduced macrophage apoptosis exacerbates epithelial inflammation and apoptosis; macrophage inflammation or ferroptosis can further promote epithelial ferroptosis or inflammatory responses. Ferroptosis in airway epithelial cells aggravates their own pyroptosis, and pyroptotic epithelial cells secrete exosomes that induce macrophage pyroptosis. NETotic neutrophils release extracellular DNA, driving inflammation in airway epithelia. Therapeutically, current exploratory strategies target these death pathways through diverse approaches, including existing pharmaceuticals, hormones, phytochemicals, recombinant proteins and nucleic acids, stem cell and regenerative therapies, and modulation of the airway microbiome. Deciphering the RCD network in COPD not only enhances our understanding of disease heterogeneity but also paves the way for developing precision therapeutics.

ID: 41808488
Title: Regulated neuronal death in Alzheimer's disease: Crosstalk and convergence of apoptosis, pyroptosis, senescence, and ferroptosis.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. Despite its rapidly increasing global prevalence, effective disease-modifying therapies remain limited. Neuronal loss is a central pathological hallmark of AD, yet classical proteinopathy frameworks centered on amyloid-β (Aβ) deposition and tau hyperphosphorylation do not fully explain the extent and dynamics of neurodegeneration. Convergent upstream pressures-including Aβ/tau-associated proteotoxicity, mitochondrial dysfunction and oxidative stress, glucose hypometabolism/brain insulin resistance, and chronic neuroinflammation-lower the threshold for regulated neuronal death programs. Evidence from human postmortem brains and experimental AD models implicates multiple death modalities, including apoptosis, inflammasome-associated pyroptosis, cellular senescence with a senescence-associated secretory phenotype (SASP), and ferroptosis driven by iron-dependent lipid peroxidation. These signatures are often mixed and show region- and stage-dependent patterns, reflecting context- and model-specific drivers rather than mutually exclusive pathways. A crosstalk-and-convergence view highlights shared hubs-oxidative stress, mitochondrial failure, inflammasome/cytokine signaling, and SASP-mediated chronic inflammation-that connect these modalities through feed-forward loops, helping to explain the limited durability of single-pathway interventions. This review summarizes recent advances across these four pathways, discusses their mechanistic interplay, and outlines translational considerations (blood-brain barrier delivery, target specificity, and limited clinical evidence). We also highlight priorities for future work, including single-cell/spatial profiling, multi-omics integration, and biomarker-guided stratification to enable rational combination strategies.

ID: 41911441
Title: Incense Aerosol-Induced Neurotoxicity Disrupts α-Synuclein Homeostasis in a Cellular Parkinson's Disease Model, Distinct from Cigarette Aerosols.
Abstract: Incense burning is a widespread indoor combustion practice, yet its neurotoxic potential and impact on α-synuclein (α-Syn) proteostasis remain poorly defined. Using SH-SY5Y cells overexpressing α-Syn as a cellular Parkinson's disease model, we exposed cells to size-fractionated incense aerosol extracts (IAE) prepared as organic-phase (OP) or water-soluble phase (WP). α-Syn overexpression augmented vulnerability to IAE, producing greater losses in viability and pronounced increases in intracellular hydrogen peroxide (H2O2), mitochondrial membrane potential depolarization, and engagement of programmed cell-death pathways. Live-cell fluorescence cross-correlation spectroscopy (FCCS) revealed that both OP-IAE and WP-IAE shifted α-Syn from oligomeric to monomeric states in the cytosol, indicating disruption of oligomerization equilibrium. Antioxidant intervention revealed mechanistic differences compared with other indoor air pollutants, cigarette smoke. OP-IAE-induced cytotoxicity cannot be mitigated by N-acetylcysteine (NAC) or rutin, whereas WP-IAE-induced toxicity was partially attenuated, with NAC surpassing rutin. By contrast, for cigarette aerosol extracts (CAE), both OP- and WP-CAEs were robustly rescued by NAC and, to a lesser extent, rutin. Together, these results indicate that incense aerosols, particularly OP-IAE, engage reactive oxygen species (ROS)-linked mitochondrial injury and programmed cell-death pathways while uniquely driving α-Syn monomerization, while exhibiting relative resistance to classical antioxidant intervention compared with cigarette aerosols. This work points out incense smoke as a distinct indoor neurotoxicant with implications for α-Syn homeostasis and Parkinsonian risk in exposed populations.

ID: 41921866
Title: High-throughput RNA sequencing identifies hub genes and anti-inflammatory effects of β-caryophyllene in cerebral ischemia-reperfusion via p38MAPK/NF-κB modulation.
Abstract: β-caryophyllene (BCP) has been shown to alleviate neurological deficits in rats with cerebral ischemia-reperfusion injury (CIRI) induced by middle cerebral artery occlusion (MCAO). However, its molecular targets remain unclear. In this study, transcriptome analysis was conducted to identify BCP-responsive genes and potential therapeutic pathways. RNA sequencing revealed that BCP downregulated genes upregulated by CIRI, particularly those involved in extracellular matrix organization, leukocyte migration, angiogenesis regulation, and reactive oxygen species metabolism. KEGG analysis indicated enrichment in the MAPK, NF-κB, and HIF-1 signaling pathways. Male SD rats were randomly divided into Sham, CIRI, CIRI+BCP (306 mg/kg), CIRI+BCP+Diprovocim, and Diprovocim-only groups. After 1.5 h of ischemia followed by 24 h of reperfusion, neurological scores, infarct volume, MAPK/NF-κB protein expression (by Western blot), hippocampal neuron damage (by HE staining), proinflammatory cytokine levels (TNF-α and IL-1β via ELISA), and oxidative stress markers (SOD and MDA) were evaluated. BCP treatment significantly reduced infarct volume, improved neurological function, downregulated MAPK and NF-κB expression, suppressed TNF-α and IL-1β release, and reduced neuronal death (all P < 0.05). These effects were partially reversed by the MAPK agonist Diprovocim, suggesting the involvement of the p38MAPK/NF-κB pathway in BCP's protective mechanism. In conclusion, BCP confers neuroprotection in CIRI by modulating key signaling pathways, particularly p38MAPK/NF-κB, highlighting its therapeutic potential in ischemic stroke.

ID: 41941350
Title: Dual Energy Depletion by Zinc/Copper Disruptor to Potentiate Cuproptosis and Pyroptosis for Enhanced Tumor Immunotherapy.
Abstract: Metal ion interference therapy disrupts ion homeostasis to stimulate immunity, but the underlying mechanisms remain poorly elucidated. Here, a hydrazide hyaluronan-decorated copper/zinc disruptor is constructed to inhibit tumoral energy metabolism and activate anticancer immunity. Functionally, Zn2+ acts as a metabolic inhibitor to suppress glycolysis by directly restraining lactate dehydrogenase activity and downregulating the PI3K/Akt/HIF-1α axis, thus reducing lactate output and limiting adenosine triphosphate generation. In parallel, Cu2+ triggers cuproptosis via mitochondrial proteotoxicity and lipoylated protein aggregation, thereby blocking the flux of pyruvate into the tricarboxylic acid cycle and aggravating energy exhaustion. This metabolic collapse forms a mechanistic cascade, in which glycolytic inhibition predisposes cells to cuproptotic stress, while cuproptosis further reinforces pyroptotic activation. Ultimately, ion overload, severe energy deficit, and subsequent oxidative perturbation cooperatively amplify pyroptosis-driven inflammatory cytokine release and establish a synergistic metal ion-induced immunogenic cell death pathway. In vitro studies reveal that the anticancer activity of the disruptor involves oxidative stress, mitochondrial dysfunction, and inflammatory responses. In vivo studies demonstrate that it efficiently suppresses primary and distant tumor growth and activates systemic immunity. Collectively, this bimetallic disruption strategy bridges metal therapy with immunotherapy, provides insights into the underlying molecular mechanisms, and highlights the potential of metal-based nanomedicine for tumor immunotherapy.

ID: 42017968
Title: Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer's disease.
Abstract: The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer's disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.

ID: 42094412
Title: TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.
Abstract: 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.

ID: 42117871
Title: Rapalink-1 Attenuates Oxidative-Stress-Induced Senescence in Vascular Cells in Association with Reduced NF-κB and MAPK Signaling.
Abstract: Oxidative stress contributes to vascular dysfunction and senescence-associated changes through activation of inflammatory and stress-responsive signaling pathways. Although the mammalian target of rapamycin (mTOR) integrates metabolic and redox-related signals, its role in vascular stress responses remains incompletely understood. In this study, we investigated the effects of Rapalink-1, an mTOR inhibitor, on H2O2-induced injury responses in human vascular endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs). Oxidative stress-associated changes were assessed using oxidation-sensitive fluorescence, DNA damage markers (γ-H2AX and 8-OHDG), and senescence-associated readouts (SA-β-gal, Lamin B1, and p21). Senescence-associated secretory phenotype (SASP)-related factors were analyzed by qPCR and Western blot, and mTOR-, NF-κB-, and MAPK-related signaling was evaluated by Western blotting. H2O2 exposure reduced cell viability and increased oxidative stress-associated readouts, DNA damage markers, senescence-associated changes, and SASP-related factor expression in both HUVECs and SMCs. Rapalink-1 attenuated many of these responses, including oxidation-sensitive fluorescence, γ-H2AX and 8-OHDG staining, SA-β-gal positivity, Lamin B1 loss, p21 upregulation, and the expression of inflammatory and matrix-remodeling factors. These effects were accompanied by reduced phosphorylation of p65, p38, ERK1/2, S6, and 4EBP1. Overall, Rapalink-1 is associated with attenuation of oxidative stress-induced injury responses in vascular endothelial and smooth muscle cells, together with reduced NF-κB-, MAPK-, and mTOR-related signaling. These findings support further investigation of mTOR-targeted approaches in vascular aging and oxidative stress-related vascular dysfunction.

ID: 42121950
Title: Valosin-Containing Protein Contributes to Plexiform Neurofibroma Formation and Represents a Novel Therapeutic Target.
Abstract: Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). By cross-comparison of RNA sequencing and RUNX1-CHIP sequencing data on mouse PNFs, we found that transcripts encoding the NF1-interacting p97/valosin-containing protein (VCP) gene are overexpressed in PNFs. Co-immunoprecipitation confirmed that VCP bounded to neurofibromin. Western blot and immunostaining confirmed VCP overexpression in both mouse and human PNFs. Treatment of primary mouse PNF Schwann cells with CB-5083, a p97/VCP inhibitor, led to accumulation of poly-ubiquitinated proteins and generation of irresolvable proteotoxic stress. Pharmacological or genetic inhibition of VCP reduced mouse PNF cell-derived sphere number, and genetic inhibition of Vcp in Schwann cell precursors decreased tumor-like lesion numbers in a cell transplantation model. In vivo treatment with CB-5083 in Nf1fl/fl;DhhCre PNF mice significantly inhibited cell proliferation, increased cell apoptosis and reduced PNF volume. The combination with a MEK inhibitor did not increase efficacy compared to the single agent, supporting the hypothesis that VCP functions in parallel to, and may be modulated by, RAS-MAPK signaling under stress or oncogenic conditions. The significant effects of VCP inhibition in this pre-clinical study suggest a potential novel therapy for patients with PNFs.

ID: 42136278
Title: Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.
Abstract: 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-κB, 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.

ID: 42198444
Title: Physical Exercise Enhances Melatonin Effect in D-Galactose/Aluminum Chloride-Induced Alzheimer's Disease of Ovariectomized Rats: Irisin Induction Associated with Upregulation of PPAR-γ/IGF-1/BDNF and Decreasing TNF-α/p38-MAPK/NLRP3/GFAP Pathway.
Abstract: Background: Postmenopausal women are at high risk of Alzheimer's disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl3 (60 and 10 mg/kg, respectively) for 42 days. Group III-V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway.

ID: 42208333
Title: Lycopene regulates microglial M1/M2 polarization by inhibiting MAPK/NF-κB signaling and alleviates neuroinflammation.
Abstract: Persistent neuroinflammation driven by dysregulated M1/M2 polarization of microglia is recognized as a key pathological mechanism in the onset and progression of multiple central nervous system (CNS) disorders. Lycopene (LYC), an important dietary carotenoid, exhibits anti-inflammatory activity; however, its molecular mechanisms regulating microglial state and function remain incompletely understood. This study systematically evaluated the anti-neuroinflammatory and neuroprotective effects of LYC in lipopolysaccharide (LPS)-stimulated human microglia (HMC3), mouse primary microglia, and transgenic zebrafish neuroinflammation models. Results indicate that LYC suppresses LPS-induced proinflammatory phenotypes in microglia by downregulating M1-associated markers (iNOS, TNF-α, IL-1β, CD86) and upregulating M2-associated markers (TGF-β, IL-10, CD206), thereby promoting their transition to an M2-like anti-inflammatory state. In primary microglia, LYC similarly favored an M2-like phenotype and partially rescued the LPS-associated reduction in phagocytosis by increasing the fraction of phagocytic cells and enhancing per-cell microbead uptake. In coculture systems, LPS-activated HMC3 cells with LYC significantly increased the survival rate and reduced apoptosis in subchamber SH-SY5Y cells, demonstrating a marked neuroprotective effect. Mechanistically, LYC markedly reduced LPS-induced phosphorylation of p38, JNK, ERK1/2, and p65, suggesting inhibition of MAPK/NF-κB signaling activation. In vivo experiments further confirmed that LYC improved motor dysfunction in zebrafish, reduced neutrophil infiltration and brain inflammatory responses, attenuated microglia-associated inflammatory activation, and restored neuronal and synapse-related gene expression. In summary, LYC alleviates neuroinflammation and exerts neuroprotective effects by inhibiting MAPK/NF-κB signaling and rebalancing microglial M1/M2 phenotypes, providing a mechanistic basis for its potential as a therapeutic candidate targeting neuroinflammation.

ID: 42216548
Title: Molecular Mechanisms of Manganese Oxide Nanoparticles Toxicity in Brain and Other Tissues: An Overview.
Abstract: The use of manganese oxide nanoparticles (MnOxNPs) in biomedicine increases the risk of their accumulation in the body, potentially leading to toxicity in various organs and tissues. In addition, occupational exposure to MnOxNPs-containing aerosols may also occur. MnOxNPs have been shown to accumulate in the brain and induce neurobehavioral alterations. However, the specific mechanisms of MnOxNPs toxicity in the brain and other tissues remain incompletely understood. Therefore, the objective of this review is to summarize existing data on the toxicity of MnOxNPs in the brain and other tissues, and to discuss the molecular mechanisms underlying their neurotoxic effects. It has been shown that MnOxNPs induce neuronal death through induction of mitochondrial dysfunction and subsequent apoptosis, and overaccumulation of tau protein and amyloid-β. Neurotoxic effects of MnOxNPs may also be mediated by blood-brain barrier disruption, and dysregulation of dopaminergic and glutaminergic signaling. Exposure to MnOxNPs induces neuroinflammation through activation of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK) pathways in a reactive oxygen species-dependent manner. In vitro studies further demonstrate that MnOxNPs exhibit a dose-dependent cytotoxic effects in alveolar macrophages, as well as in respiratory, colonic, and other epithelial cells, through the promotion of oxidative stress and an inflammatory response. Overexposure to MnOxNPs has significant nephrotoxic, hepatotoxic, and immunotoxic effects, as well as affecting the reproductive system. Smaller particles exhibit more pronounced toxic effects in the brain and other tissues than larger nanoparticles or microparticles. However, the mechanisms underlying the different toxicities of MnOxNPs of different sizes, shapes, and surface modifications remain unclear. These observations highlight the potential of MnOxNP exposure to contribute to neurological disorders and dysfunction of other systems, underscoring the need for further mechanistic studies to ensure their safe application in biomedicine.

ID: 42261159
Title: The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?
Abstract: 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 α-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.

ID: 42296779
Title: Artemisinin and quercetin attenuate hydrogen peroxide-induced oxi-inflammatory-mitochondrial dysfunction-SASP axis mediated lung epithelial cell premature senescence via targeting Stat-1/Atm-p53/p16/p21/Bcl2, NOD-1/MAPKs/NF-κB/ signalling cascades.
Abstract: The senescence of lung epithelial cells impairs self-repair and exacerbates lung damage in idiopathic pulmonary fibrosis. The potential of natural phytochemicals to reverse premature senescence warrants investigation. Information regarding the independent multifaceted effect of quercetin and artemisinin on epithelial senescence has not been delineated yet. The present investigation aimed to comprehend their attributes on H2O2-induced hallmark of premature senescence via controlling the vicious circle of oxidative-inflammatory stress, impaired cell proliferation, apoptosis, DNA damage, and inflammatory senescence cascades. An in vitro model of H2O2-exposed BEAS-2B cells was used to explore senescence using microscopy, qRT-PCR, immunoblotting, flow cytometry, and NMR· H2O2 (100 µM) treatment induced cellular senescence-associated features without significant cytotoxicity, as evidenced by enhanced SA-β-galactosidase activity, irreversible irregular enlargement, shrinking, and flattened cell appearance, which was reversed by quercetin and artemisinin at varying degree. Results revealed that quercetin and artemisinin restored disrupted mitochondrial function in senescent cells, as evidenced by reduced MMP, GLS, ARRDC4, TXNIP, creatine, and increased NRF-2, HO-1, NQO-1, Sirt-1/5, and glycine levels. Furthermore, quercetin and artemisinin promoted proliferative ability, DNA repair, S-phase cell cycle transition, apoptosis, and suppressed SASP, as evidenced by enhanced Ki67 expression, annexin-V-positive cells, and diminished expression of interleukins, COX-2, MMPs, and the Atm/p53/p16/p21/Bcl-2 axis. Subsequently, activation of NOD-1, Stat-1, NF-κB, ERK1/2, p38, and JNK was decisively thwarted by quercetin and artemisinin. Intriguingly, Lamin B1 restoration and ROS inhibition were only noticed in quercetin, indicating both are effective in halting senescence through an alternative pathway. Overall, the present investigation emphasizes that quercetin and artemisinin exhibit both senolytic and senomorphic properties and could be valuable senotherapeutics for stress-induced premature senescence.

ID: 42348037
Title: Combined Puerarin and Magnesium Acetyl Taurate Intervention Mitigates Autism-Like Pathology Through Glutamatergic and MAPK Pathway Regulation.
Abstract: Autism is a multifactorial neurodevelopmental disorder characterized by social deficits, stereotypical behaviour, and neurotransmitter imbalance. This study evaluated the neuroprotective potential of Puerarin (PUN) and Magnesium Acetyl Taurate (MGAT) in a propionic acid (PPNA)-induced rat model of autism. PPNA was administered intracerebroventricularly for 11 consecutive days to induce autism-like features, followed by a 44-day treatment period with PUN (300 mg/kg, i.p.) and MGAT (500 mg/kg, p.o.). A comprehensive assessment was conducted, including behavioural analysis, biochemical and molecular evaluations, cerebrospinal fluid and plasma profiling, and histopathology. Treatment with PUN and MGAT, particularly in combination, improved behavioural outcomes, restored neurotransmitter balance, reduced neuroinflammation and apoptotic signaling, and attenuated activation of the glutaminase-glutamate/NMDAR and MAPK pathways (C-JNK, ERK1/2, P38 MAPK). Additionally, treatment increased magnesium levels and PSD-95 expression, indicating significant neuroprotection. These findings support the potential of PUN and MGAT as a multitarget therapeutic strategy for autism and warrant further translational investigation.

ID: 42350373
Title: Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.
Abstract: 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.

ID: 42352045
Title: Aminochrome-Induced Disruption of Autophagosome-Lysosome Fusion: Implications for Protein Aggregation in Parkinson's Disease.
Abstract: Aminochrome, an endogenous neurotoxin, has been implicated in the loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal system in Parkinson's disease. Although aminochrome-induced oxidative stress and its inhibitory effects on microtubule polymerization are well documented, its impact on protein aggregation remains poorly understood. The aim of this research was to evaluate the effects of aminochrome on protein aggregate accumulation in SH-SY5Y cells differentiated into dopaminergic neurons. While the role of aminochrome in autophagy has been described, its direct effect on autophagosome-lysosome fusion has not been studied. Our findings reveal that aminochrome, like vinblastine, delays autophagosome-lysosome fusion and induces cell death. This inhibitory effect was also observed in the presence of autophagy inducers, which partially attenuated aminochrome-induced cell death. Under these conditions of disruptions in autophagosome-lysosome fusion, a marked accumulation of perinuclear vimentin and ubiquitin aggregates was observed. Aminochrome also increased colocalization between vimentin and ubiquitin. Interestingly, ubiquitin aggregates were also detected within the nucleus. These findings suggest that aminochrome-induced disruption of the microtubule network, particularly its impairment of autophagosome-lysosome fusion and promotion of protein aggregation, may represent a critical mechanism leading to cell death. In addition, inhibition of autophagosome-lysosome fusion may contribute to the accumulation of perinuclear and nuclear protein aggregates, which may be associated with either toxic or non-toxic pathways. Our findings underscore the therapeutic potential of targeting both microtubule stabilization and proteostasis pathways, including autophagy and the ubiquitin-proteasome system (UPS), in Parkinson's disease, highlighting the need for further research into nuclear proteotoxicity mechanisms.

ID: 42352358
Title: Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP/p-Pak1-T423/p-P38-T180/pMK2-T334/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1/-2 as promising protein/peptide drugs for ALS treatment.

ID: 42365390
Title: Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.
Abstract: 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.

ID: 42413217
Title: Restoring the balance: Resistance exercise-induced insulin-like growth factor-1 restores PI3K/Akt and MAPK/ERK cross-talk to ameliorate Alzheimer's disease.
Abstract: Alzheimer's disease (AD) remains a progressive neurodegenerative disorder without effective disease-modifying therapies. Epidemiological evidence indicates that regular resistance exercise substantially reduces AD risk, an effect potentially mediated by insulin-like growth factor-1 (IGF-1). However, the complete mechanistic pathway from exercise-induced peripheral IGF-1 synthesis to its central neuroprotective actions has not been systematically integrated. This review provides a comprehensive framework linking resistance exercise to AD amelioration through IGF-1-dependent signaling. We first detail how resistance exercise stimulates IGF-1 secretion from the liver and skeletal muscle via both endocrine (GH-IGF-1 axis) and autocrine/paracrine (mechano-sensitive MGF induction) pathways. Subsequently, we delineate three complementary routes by which circulating IGF-1 enters the brain: (1) lipoprotein receptor-related protein-1(LRP-1)-mediated transcytosis across the blood-brain barrier (BBB) coupled with activity-dependent vasodilation, (2) lipoprotein receptor-related protein-2(LRP-2)-mediated transport across the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus, and (3) passive diffusion through circumventricular organs (CVOs). Once within the central nervous system, we propose that IGF-1 exerts its therapeutic effects primarily by restoring the physiological cross-inhibitory balance between the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways. Specifically, by reactivating Akt, exercise-induced IGF-1 suppresses GSK-3β-driven tau hyperphosphorylation, while simultaneously tempering pathological MAPK/ERK overactivation, thereby reducing β-amyloid (Aβ) generation and neuroinflammation. This rebalancing action further promotes Aβ clearance, enhances synaptic plasticity, and counteracts neuronal apoptosis. Notably, we critically discuss the context-dependent "double-edged sword" nature of IGF-1 signaling, where excessive or mistimed activation may exacerbate late-stage pathology, underscoring the need for stage-specific interventions. In summary, this review integrates the peripheral synthesis, multi-route central delivery, and pathway-rebalancing mechanisms of exercise-induced IGF-1, providing a mechanistic rationale for personalized resistance exercise prescriptions as a non-pharmacological strategy to combat AD.

ID: 42495541
Title: Tuberostemonine ameliorates Alzheimer's disease pathology by suppression of the p38 MAPK signaling pathway.
Abstract: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with limited therapeutic options. Here, we report that tuberostemonine (Tub), an alkaloid from Stemona tuberosa, exerts neuroprotective effects in AD models. In Aβ1-42-treated PC12 cells, Tub reduced cytotoxicity, apoptosis, and oxidative stress while restoring mitochondrial function. In APP/PS1 transgenic mice, Tub administration improved cognitive performance, reduced amyloid-β plaque deposition, attenuated microglial activation, and attenuated neuronal loss, with efficacy superior to donepezil. Mechanistically, Tub selectively inhibited p38 MAPK phosphorylation without affecting ERK or JNK pathways, as confirmed by pharmacological inhibition and activation experiments. These findings identify Tub as a promising multi-target natural compound for AD intervention through p38 MAPK pathway modulation.