# PathMap Report Trace Context: #00000125
Hypothesis: Discovery: Considering PubMed #37563705, #42012729, and #42541426, Spermidine is a known inducer of autophagy through EP300 inhibition and TFEB activation. Since TMEM106B amylofilaments induce lysosomal dysfunction, TFEB-driven restoration of lysosomal capacity would logically prevent the accumulation of these filaments.
Author: Joshua Dungan (PathMap.org)
License: 'THE GLOBAL HUMANITARIAN PROPRIETARY LICENSE (VERSION 1.0.1)' https://pathmap.org/license.pdf
Full provenance JSON trace: https://pathmap.org/download.php/?id=125
==================================================

SYSTEM NOTE: The eight-digit ID numbers (e.g., ID 12345678) used in citations below are PubMed ID numbers and can be loaded via https://pubmed.ncbi.nlm.nih.gov/{ID}/ for verification.

==================================================

## Primary Synthesis & Clinical Bottom-Line
Scientific literature identifies spermidine as a polyamine capable of modulating autophagy via EP300 inhibition and subsequent TFEB nuclear translocation. Concurrently, TMEM106B has been characterized as a transmembrane lysosomal protein that forms amyloid filaments in an age-dependent manner. This synthesis evaluates whether TFEB-mediated lysosomal restoration can mitigate the pathological accumulation of TMEM106B amyloids.

## Plausibility Verdicts
- Evaluation 1: Yes, spermidine-induced TFEB activation is a proven mechanism for enhancing lysosomal function. While TMEM106B amyloid accumulation is associated with lysosomal dysfunction, the direct clearance of these specific filaments by spermidine-mediated TFEB activation has not been definitively demonstrated.

## Novel & Overlooked Insights
- Spermidine supplementation acts as a downstream effector of the anti-aging effects induced by fasting and rapamycin.
- TMEM106B amyloid filaments demonstrate age-dependent formation in astrocytes and reside in endosomal/lysosomal compartments.
- TFEB phase separation is essential for its transcriptional activation and anti-inflammatory functions induced by nutrient stress.
- The TFEB-ATP6V0C axis is a critical determinant of microglial proteostasis and alpha-synuclein clearance.
- TMEM106B single nucleotide polymorphisms are associated with cognitive resilience in Alzheimer's disease cases, independent of amyloid plaque burden.
- Spermidine-induced autophagy via TFEB can rescue mitochondrial function in several cell types, including Sertoli cells and cardiomyocytes.
- The induction of ER-phagy via FAM134B is transcriptionally regulated by TFEB/TFE3, creating a secondary layer of proteostasis regulation.

## Extracted Custom Discoveries
### Suggested Experiments
- Determine if spermidine or TFEB overexpression accelerates the degradation rate of TMEM106B filaments in primary neuronal culture models.
- Assess whether TFEB knockdown increases TMEM106B amyloid burden in microglia during aging-induced stress.

### Suggested Studies
- Longitudinal analysis of CSF TMEM106B levels in individuals undergoing long-term spermidine supplementation.
- Comparative proteomics of lysosomal contents in patients with high vs. low TMEM106B aggregate burden treated with autophagy-inducing agents.

### Swansons Literature Based Discovery Candidates
- Spermidine-mediated TFEB activation may modulate the biophysical properties of the Biondi body variant of TMEM106B filaments to reduce amyloid burden.
- Spermidine/TFEB axis (Source #42588134, #42012729)
- TMEM106B amyloid filaments in Biondi bodies (Source #39503754, #38886865)
- Lysosomal degradative capacity and acidification (Source #42546981)
- TFEB is the master regulator of lysosomal biogenesis; since Biondi bodies are amyloid inclusions found within secondary lysosomes, enhancing lysosomal degradative capacity via TFEB activation provides a logical mechanism to influence their clearance.

### Contradictions Between Evidences
- None identified in the provided text, though the 'double-edged' role of autophagy in tumor survival vs. suppression is noted.

### Repurposed Solutions
- The use of TFEB activators, such as spermidine or the curcumin analog CM-C1, serves as a multipurpose strategy to restore autophagic flux in conditions ranging from neurodegeneration to inflammatory bowel disease.

## Evaluation Scoring Reference
All analyzed perspectives utilize a standardized 1-7 scoring framework:
- Alignment Score (1-7): How well does the evaluated claim factually align with the provided evidence set?
  [1 = Evidence proves claim strictly false, 2 = Evidence indicates the claim is impossible, 3 = Implausible, 4 = Neutral/Unrelated, 5 = Plausible, 6 = Evidence indicates inevitable, 7 = Evidence proves claim strictly true]
- Consilience Score (1-7): How consilient (in agreement) is the evidence set regarding this claim?
  [1 = Highly Conflicting/Disputed, 4 = Mixed, 7 = Unanimous Agreement]
- Confidence Score (1-7): Implied confidence of the research based on study design and depth.
  [1 = In Vitro/Animal/Preprint, 4 = Observational/Moderate, 7 = Meta-analysis/RCT]

## Evaluated Perspectives & Findings
### Perspective R1: Claim [Run1 Eval1 Synthesis] evaluated against Evidence [N/A]
- Alignment Score: 5/7
- Consilience Score: 6/7
- Directional Logic: High Score = SUPPORTS Original Claim
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.

###[CLAIM EVALUATED AND ANSWER TO USER]
"Discovery: Considering PubMed #37563705, #42012729, and #42541426, Spermidine is a known inducer of autophagy through EP300 inhibition and TFEB activation. Since TMEM106B amylofilaments induce lysosomal dysfunction, TFEB-driven restoration of lysosomal capacity would logically prevent the accumulation of these filaments."

### [ABSTRACT & REWRITTEN CLAIM]
Scientific literature identifies spermidine as a polyamine capable of modulating autophagy via EP300 inhibition and subsequent TFEB nuclear translocation. Concurrently, TMEM106B has been characterized as a transmembrane lysosomal protein that forms amyloid filaments in an age-dependent manner. This synthesis evaluates whether TFEB-mediated lysosomal restoration can mitigate the pathological accumulation of TMEM106B amyloids.

### [INTRODUCTION & JUSTIFICATION]
Spermidine, a naturally occurring polyamine, has emerged as a candidate modulator of brain aging because it regulates autophagy, mitochondrial function, oxidative balance, and neuroinflammatory signaling. The mechanism by which spermidine promotes longevity and cellular health is largely attributed to its ability to induce macroautophagy. Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies. This pathway involves the hypusination of EIF5A, which facilitates the translation of TFEB, a master regulator of lysosomal biogenesis and autophagic flux. 

Regarding lysosomal pathology, TMEM106B inclusions have been identified as amyloids in aging and neurodegeneration. By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes. While the data suggests that TMEM106B filaments form in an age-dependent manner, the potential for TFEB-mediated clearance remains a hypothesized therapeutic intersection. Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models. Therefore, the activation of TFEB through spermidine supplementation presents a plausible theoretical mechanism to support the degradation of aberrant lysosomal proteins, including TMEM106B aggregates.

### [DISCUSSION: NOVEL & OVERLOOKED]
*   Spermidine supplementation acts as a downstream effector of the anti-aging effects induced by fasting and rapamycin.
*   TMEM106B amyloid filaments demonstrate age-dependent formation in astrocytes and reside in endosomal/lysosomal compartments.
*   TFEB phase separation is essential for its transcriptional activation and anti-inflammatory functions induced by nutrient stress.
*   The TFEB-ATP6V0C axis is a critical determinant of microglial proteostasis and alpha-synuclein clearance.
*   TMEM106B single nucleotide polymorphisms are associated with cognitive resilience in Alzheimer's disease cases, independent of amyloid plaque burden.
*   Spermidine-induced autophagy via TFEB can rescue mitochondrial function in several cell types, including Sertoli cells and cardiomyocytes.
*   The induction of ER-phagy via FAM134B is transcriptionally regulated by TFEB/TFE3, creating a secondary layer of proteostasis regulation.

### [EVIDENCE, METHODOLOGY & CITATIONS]
1. ID: 42588134 - Application: Spermidine mechanism - "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
2. ID: 42222188 - Application: SPD function - "SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
3. ID: 42012729 - Application: Spermidine and aging - "Spermidine, a naturally occurring polyamine, has emerged as a candidate modulator of brain aging because it regulates autophagy, mitochondrial function, oxidative balance, and neuroinflammatory signaling."
4. ID: 39212197 - Application: Fasting-induced surge - "Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies."
5. ID: 42224830 - Application: Autophagy decline - "Molecularly, dysregulation of nutrient-sensing pathways such as AMPK and mTOR, impaired transcriptional control by TFEB and FOXO, and reduced lysosomal competence contribute to the reduction of autophagy."
6. ID: 38886865 - Application: TMEM106B characterization - "We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids."
7. ID: 39503754 - Application: Biondi bodies and lysosomes - "By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes."
8. ID: 42546981 - Application: Lysosomal restoration potential - "Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models."
9. ID: 41874700 - Application: eIF5A/TFEB translation - "Our review highlights that spermidine and one of its major cellular targets, translation initiation factor 5A (eIF5A), facilitate translation of transcription factor EB (TFEB) to induce autophagy during starvation."
10. ID: 39729151 - Application: TFEB phase separation - "More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis."
11. ID: 42239088 - Application: TFEB in PTX models - "The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, was also upregulated in the nucleus of cultured mouse DRG neurons treated with PTX."
12. ID: 42172896 - Application: PQLC2/TFEB interaction - "PQLC2-deficient cells exhibited enhanced nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome, accompanied by increased expression of TFEB-lysosomal and autophagy target genes."
13. ID: 42169618 - Application: TFEB targets - "Single-cell RNA-seq after treatment revealed increased expression of TFEB targets and autophagy-related genes in B cells, in line with elevated autophagic flux."
14. ID: 42424320 - Application: TFEB in neuropathy - "Transcriptomic analysis reveals dysregulation of autophagy-related transcription factors, notably TFEB, FOXO3, and NRF2."
15. ID: 42501331 - Application: GBP4 mechanism - "GBP4 facilitates Mtb containment by promoting lysosomal acidification and autophagy via type Ⅰ IFN-dependent TFEB and FOXO3a activation."
16. ID: 42299666 - Application: TFEB cardiac function - "Our findings demonstrate that TFEB antagonizes pathological hypertrophic cardiac remodeling through upregulation of lysosomal capacity, maintaining mitochondrial energetic function, and promoting AMPK signaling."
17. ID: 42251851 - Application: Mestranol/TFEB - "Transcriptomic profiling of flow‑sorted macrophage/microglia populations reveals coordinated down‑regulation of lysosomal-phagosomal and immune gene networks, including MIT/TFE family transcription factors (TFEB/TFEC) and immune master regulators such as SPI1, IRFs, BATF, MAFB, and RUNX3."
18. ID: 42217339 - Application: Spermidine/AMPK/Mitophagy - "Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis"
19. ID: 42117833 - Application: miR-214/TFEB - "Further analysis revealed that miR-214-3p directly reversed the lysosomal defects triggered by IMI treatment."
20. ID: 42086115 - Application: Spermidine resilience - "Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience"
21. ID: 42061637 - Application: TPhP mechanism - "The results indicate that TPhP exerts hepatotoxicity through multi-target interactions derived from network analysis, primarily involving PPARG/PI3K/AKT1-driven metabolic dysregulation and STAT3/mTORC1-mediated inflammatory cascades associated with PTGS2."
22. ID: 42013738 - Application: SICM/SPD - "SPD markedly attenuated SICM in vivo and in vitro by improving both mitochondrial quantity and quality."
23. ID: 42508389 - Application: Sarcopenia framework - "Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation."
24. ID: 42264187 - Application: CRM nanodelivery - "Consequently, CRMs such as metformin, spermidine, and curcumin have been widely used because of their ability to recapitulate key molecular effects of CR."
25. ID: 41825683 - Application: ALA-PDT autophagy - "ALA-PDT activates antibacterial autophagy via the ROS-EP300 pathway to eliminate intracellular M. abscessus"
26. ID: 41756429 - Application: SAT1/α-Syn - "SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening."
27. ID: 41695269 - Application: ALS/RCD - "Integrated bibliometric and bioinformatics evidence supports an immunometabolic convergence involving ferroptosis-inflammation-autophagy signaling"
28. ID: 41614028 - Application: DCM biomarkers - "These findings highlight their diagnostic potential for DCM with HF and lay a foundation for exploring targeted small-molecule therapies (e.g., QL-XII-47, tipifarnib-P2) to improve the disease's clinical management."
29. ID: 41497595 - Application: Lysosomal escape - "Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43."
30. ID: 41463395 - Application: TANGO2 modifiers - "These findings highlight lipid metabolism as a key pathway in TANGO2 deficiency pathophysiology and suggest autophagy and mitophagy as additional modifier mechanisms influencing phenotypic variability."
31. ID: 41415834 - Application: Fructose/MASLD - "Fructose-SB uniquely accelerates MASLD progression in HFHC-fed mice through transcriptional reprogramming of metabolic and mitochondrial pathways."
32. ID: 41330616 - Application: PD-1/Spermidine - "Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis."
33. ID: 41315858 - Application: AD phagocytosis - "Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2."
34. ID: 40760677 - Application: NORAD/ferroptosis - "NORAD is a promoter of oncogenesis and inhibited ferroptosis via miR-144-3p-mTOR-ferritinophagy in cancer cells."
35. ID: 40667544 - Application: SF3b4/CRC - "SF3b4 may promote CRC proliferation by enhancing cellular autophagy."
36. ID: 40096894 - Application: EP300/SIRT5 - "Activation of EP300 expression increased SIRT5 expression and significantly improved autophagy for inhibition of NPC senescence."
37. ID: 39873130 - Application: CCFE/sarcopenia - "CCFE enhanced autophagy by activating AMPK (80% increase, p < 0.01) and inhibiting Atg5 protein acetylation (65% decrease, p < 0.001), with contributions from ellagic acid and polyamines."
38. ID: 39480813 - Application: TMEM106B/SARS-CoV-2 - "SARS-CoV-2MA1 infection in HEK293T cells relies on heparan sulfate and endocytic pathways, with TMEM106B, a transmembrane lysosomal protein, the most significant contributor."
39. ID: 39262221 - Application: TMEM106B/CR - "TMEM106B variants may influence CR independent of AD pathology."
40. ID: 42429378 - Application: Ureaplasma pH adaptation - "The findings of this study suggest a multi-omics scheme for how organisms adapt to environmental changes and ensure survival without inducing new circuits or complex transcriptional regulation."
41. ID: 42374161 - Application: TFEB-ATP6V0C - "These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression."
42. ID: 42368585 - Application: GRg1/CKLF1 - "Mechanistically, GRg1 binds to CKLF1 and modulates the mTORC1/TFEB pathway, enhancing lysosomal function and thereby facilitating the clearance of dead/dying neurons."
43. ID: 42331842 - Application: Placental autophagy - "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
44. ID: 42165414 - Application: HFD/STAT3-TFEB - "HFD in vivo and PA in vitro disrupt lysosomal function and the intestinal barrier through the STAT3-TFEB axis, suggesting this signaling pathway as a promising avenue for intervention in diet-associated IBD."
45. ID: 42107477 - Application: Nano-Se/Cd - "This present study provides a foundation for preclinical research for its usefulness as a potential therapeutic for reproductive toxicity induced by environmental heavy metal pollutants."
46. ID: 42104568 - Application: PACS2/ER-phagy - "Our findings demonstrate that SIM is closely associated with disrupted MAM integrity."
47. ID: 42104376 - Application: VPS13B/lysosome - "Together, these findings identify VPS13B as a regulator of lysosomal homeostasis and provide insight into how VPS13B deficiency may contribute to Cohen syndrome pathology."
48. ID: 42479943 - Application: Aging kidneys/TFEB - "Overexpression of TFEB could partially restore autophagic activity in senescent renal tubular cells and protect them from LPS-induced damage."
49. ID: 42468217 - Application: Oocyte toxicity - "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
50. ID: 42424320 - Application: Neuropathy mechanisms - "These findings provide new insights into the molecular mechanisms underlying diabetic neuropathy and highlight promising avenues for therapeutic intervention, potentially leading to improved management strategies for this challenging complication."



## Logical Systems Map (Logical Gates)
- "Spermidine" -> "Transcription Factor EB"
- "Transcription Factor EB" -> "Lysosomes"
- "Lysosomes" -> "TMEM106B protein"

## Verified Verbatim Quotes
- "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
- "SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
- "We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids."
- "By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes."
- "Spermidine, a naturally occurring polyamine, has emerged as a candidate modulator of brain aging because it regulates autophagy, mitochondrial function, oxidative balance, and neuroinflammatory signaling."
- "Molecularly, dysregulation of nutrient-sensing pathways such as AMPK and mTOR, impaired transcriptional control by TFEB and FOXO, and reduced lysosomal competence contribute to the reduction of autophagy."
- "Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models."
- "Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies."
- "HFD in vivo and PA in vitro disrupt lysosomal function and the intestinal barrier through the STAT3-TFEB axis, suggesting this signaling pathway as a promising avenue for intervention in diet-associated IBD."
- "Current evidence, particularly from animal and mechanistic studies, suggests that exercise and cold exposure may regulate MASLD-related metabolic abnormalities through the AMPK/ACC/SREBP1c, AMPK/SIRT1/PGC-1α and AMPK/mTOR/TFEB pathways"
- "This review identifies lysosomal restoration as a potential therapeutic intervention point for overcoming downstream autophagic impairment in G-OA."
- "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
- "Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan."
- "These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models"
- "Mechanistically, GRg1 binds to CKLF1 and modulates the mTORC1/TFEB pathway, enhancing lysosomal function and thereby facilitating the clearance of dead/dying neurons."
- "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
- "Our findings demonstrate that TFEB antagonizes pathological hypertrophic cardiac remodeling through upregulation of lysosomal capacity, maintaining mitochondrial energetic function, and promoting AMPK signaling."
- "Mestranol exposure causes pronounced microglia hypertrophy and reduces neutral red staining, without affecting microglia number or neuronal apoptosis."
- "The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, was also upregulated in the nucleus of cultured mouse DRG neurons treated with PTX."
- "Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis"
- "PQLC2-deficient cells exhibited enhanced nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome, accompanied by increased expression of TFEB-lysosomal and autophagy target genes."
- "Single-cell RNA-seq after treatment revealed increased expression of TFEB targets and autophagy-related genes in B cells, in line with elevated autophagic flux."
- "Further analysis revealed that miR-214-3p directly reversed the lysosomal defects triggered by IMI treatment."
- "Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience"
- "The results indicate that TPhP exerts hepatotoxicity through multi-target interactions derived from network analysis, primarily involving PPARG/PI3K/AKT1-driven metabolic dysregulation and STAT3/mTORC1-mediated inflammatory cascades associated with PTGS2."
- "SPD markedly attenuated SICM in vivo and in vitro by improving both mitochondrial quantity and quality."
- "Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation."
- "Consequently, CRMs such as metformin, spermidine, and curcumin have been widely used because of their ability to recapitulate key molecular effects of CR."
- "Our review highlights that spermidine and one of its major cellular targets, translation initiation factor 5A (eIF5A), facilitate translation of transcription factor EB (TFEB) to induce autophagy during starvation."
- "ALA-PDT activates antibacterial autophagy via the ROS-EP300 pathway to eliminate intracellular M. abscessus"
- "SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening."
- "Integrated bibliometric and bioinformatics evidence supports an immunometabolic convergence involving ferroptosis-inflammation-autophagy signaling"
- "These findings highlight their diagnostic potential for DCM with HF and lay a foundation for exploring targeted small-molecule therapies (e.g., QL-XII-47, tipifarnib-P2) to improve the disease's clinical management."
- "Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43."
- "These findings highlight lipid metabolism as a key pathway in TANGO2 deficiency pathophysiology and suggest autophagy and mitophagy as additional modifier mechanisms influencing phenotypic variability."
- "Fructose-SB uniquely accelerates MASLD progression in HFHC-fed mice through transcriptional reprogramming of metabolic and mitochondrial pathways."
- "Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis."
- "Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2."
- "NORAD is a promoter of oncogenesis and inhibited ferroptosis via miR-144-3p-mTOR-ferritinophagy in cancer cells."
- "SF3b4 may promote CRC proliferation by enhancing cellular autophagy."
- "Activation of EP300 expression increased SIRT5 expression and significantly improved autophagy for inhibition of NPC senescence."
- "CCFE enhanced autophagy by activating AMPK (80% increase, p < 0.01) and inhibiting Atg5 protein acetylation (65% decrease, p < 0.001), with contributions from ellagic acid and polyamines."
- "More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis."
- "SARS-CoV-2MA1 infection in HEK293T cells relies on heparan sulfate and endocytic pathways, with TMEM106B, a transmembrane lysosomal protein, the most significant contributor."
- "TMEM106B variants may influence CR independent of AD pathology."
- "Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation."
- "The findings of this study suggest a multi-omics scheme for how organisms adapt to environmental changes and ensure survival without inducing new circuits or complex transcriptional regulation."
- "Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies."
- "SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation."
- "Spermidine, a naturally occurring polyamine, has emerged as a candidate modulator of brain aging because it regulates autophagy, mitochondrial function, oxidative balance, and neuroinflammatory signaling."
- "Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies."
- "Molecularly, dysregulation of nutrient-sensing pathways such as AMPK and mTOR, impaired transcriptional control by TFEB and FOXO, and reduced lysosomal competence contribute to the reduction of autophagy."
- "We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids."
- "By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes."
- "Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models."
- "Our review highlights that spermidine and one of its major cellular targets, translation initiation factor 5A (eIF5A), facilitate translation of transcription factor EB (TFEB) to induce autophagy during starvation."
- "More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis."
- "The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, was also upregulated in the nucleus of cultured mouse DRG neurons treated with PTX."
- "PQLC2-deficient cells exhibited enhanced nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome, accompanied by increased expression of TFEB-lysosomal and autophagy target genes."
- "Single-cell RNA-seq after treatment revealed increased expression of TFEB targets and autophagy-related genes in B cells, in line with elevated autophagic flux."
- "Transcriptomic analysis reveals dysregulation of autophagy-related transcription factors, notably TFEB, FOXO3, and NRF2."
- "GBP4 facilitates Mtb containment by promoting lysosomal acidification and autophagy via type Ⅰ IFN-dependent TFEB and FOXO3a activation."
- "Our findings demonstrate that TFEB antagonizes pathological hypertrophic cardiac remodeling through upregulation of lysosomal capacity, maintaining mitochondrial energetic function, and promoting AMPK signaling."
- "Transcriptomic profiling of flow‑sorted macrophage/microglia populations reveals coordinated down‑regulation of lysosomal-phagosomal and immune gene networks, including MIT/TFE family transcription factors (TFEB/TFEC) and immune master regulators such as SPI1, IRFs, BATF, MAFB, and RUNX3."
- "Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis"
- "Further analysis revealed that miR-214-3p directly reversed the lysosomal defects triggered by IMI treatment."
- "Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience"
- "The results indicate that TPhP exerts hepatotoxicity through multi-target interactions derived from network analysis, primarily involving PPARG/PI3K/AKT1-driven metabolic dysregulation and STAT3/mTORC1-mediated inflammatory cascades associated with PTGS2."
- "SPD markedly attenuated SICM in vivo and in vitro by improving both mitochondrial quantity and quality."
- "Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation."
- "Consequently, CRMs such as metformin, spermidine, and curcumin have been widely used because of their ability to recapitulate key molecular effects of CR."
- "ALA-PDT activates antibacterial autophagy via the ROS-EP300 pathway to eliminate intracellular M. abscessus"
- "SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening."
- "Integrated bibliometric and bioinformatics evidence supports an immunometabolic convergence involving ferroptosis-inflammation-autophagy signaling"
- "These findings highlight their diagnostic potential for DCM with HF and lay a foundation for exploring targeted small-molecule therapies (e.g., QL-XII-47, tipifarnib-P2) to improve the disease's clinical management."
- "Transient lysosomal injury markedly enhanced neoaggregation and loss of function, likely by promoting fibril interactions with native TDP-43."
- "These findings highlight lipid metabolism as a key pathway in TANGO2 deficiency pathophysiology and suggest autophagy and mitophagy as additional modifier mechanisms influencing phenotypic variability."
- "Fructose-SB uniquely accelerates MASLD progression in HFHC-fed mice through transcriptional reprogramming of metabolic and mitochondrial pathways."
- "Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis."
- "Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2."
- "NORAD is a promoter of oncogenesis and inhibited ferroptosis via miR-144-3p-mTOR-ferritinophagy in cancer cells."
- "SF3b4 may promote CRC proliferation by enhancing cellular autophagy."
- "Activation of EP300 expression increased SIRT5 expression and significantly improved autophagy for inhibition of NPC senescence."
- "CCFE enhanced autophagy by activating AMPK (80% increase, p < 0.01) and inhibiting Atg5 protein acetylation (65% decrease, p < 0.001), with contributions from ellagic acid and polyamines."
- "SARS-CoV-2MA1 infection in HEK293T cells relies on heparan sulfate and endocytic pathways, with TMEM106B, a transmembrane lysosomal protein, the most significant contributor."
- "TMEM106B variants may influence CR independent of AD pathology."
- "The findings of this study suggest a multi-omics scheme for how organisms adapt to environmental changes and ensure survival without inducing new circuits or complex transcriptional regulation."
- "These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression."
- "Mechanistically, GRg1 binds to CKLF1 and modulates the mTORC1/TFEB pathway, enhancing lysosomal function and thereby facilitating the clearance of dead/dying neurons."
- "In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production."
- "HFD in vivo and PA in vitro disrupt lysosomal function and the intestinal barrier through the STAT3-TFEB axis, suggesting this signaling pathway as a promising avenue for intervention in diet-associated IBD."
- "This present study provides a foundation for preclinical research for its usefulness as a potential therapeutic for reproductive toxicity induced by environmental heavy metal pollutants."
- "Our findings demonstrate that SIM is closely associated with disrupted MAM integrity."
- "Together, these findings identify VPS13B as a regulator of lysosomal homeostasis and provide insight into how VPS13B deficiency may contribute to Cohen syndrome pathology."
- "Overexpression of TFEB could partially restore autophagic activity in senescent renal tubular cells and protect them from LPS-induced damage."
- "Spermidine supplementation effectively restored autophagic activity and rescued the associated cellular defects, thereby improving both nuclear and cytoplasmic maturation in oocytes."
- "These findings provide new insights into the molecular mechanisms underlying diabetic neuropathy and highlight promising avenues for therapeutic intervention, potentially leading to improved management strategies for this challenging complication."