bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–02–16
57 papers selected by
Viktor Korolchuk, Newcastle University
  1. Mechanisms and roles of membrane-anchored ATG8s.
  2. Canonical and noncanonical autophagy: involvement in Parkinson's disease.
  3. Transcriptional repression of autophagy and lysosome biogenesis.
  4. Ezrin defines TSC complex activation at endosomal compartments through EGFR-AKT signaling.
  5. Hyperosmotic Stress Promotes the Nuclear Translocation of TFEB in Tubular Epithelial Cells Depending on Intracellular Ca2+ Signals via TRPML Channels.
  6. Advancements in autophagy perturbations in Alzheimer's disease: Molecular aspects and therapeutics.
  7. Buddleoside alleviates nonalcoholic steatohepatitis by targeting the AMPK-TFEB signaling pathway.
  8. The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux.
  9. Retinal Pigment Epithelium Under Oxidative Stress: Chaperoning Autophagy and Beyond.
  10. Development of selective deconjugases for membrane-anchored LC3A/B in post-mitotic neurons.
  11. Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.
  12. Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target.
  13. Aging, cancer, and autophagy: connections and therapeutic perspectives.
  14. Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.
  15. Transcriptional regulation of autophagy in skeletal muscle stem cells.
  16. The role of autophagy in fibrosis: Mechanisms, progression and therapeutic potential (Review).
  17. Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity.
  18. Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.
  19. NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome.
  20. Next generation lysosome: Brought to you by cGAS-STING.
  21. The Yeast-Fermented Garlic and a Balance of Spermine/Spermidine Activates Autophagy via EGR1 Transcriptional Factor.
  22. FBXL4-Related Mitochondrial Depletion Syndrome Underscores the role of Mitophagy in Stem Cell Differentiation during Embryogenesis.
  23. PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma.
  24. Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.
  25. Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.
  26. Bafilomycin A1 induces colon cancer cell death through impairment of the endolysosome system dependent on iron.
  27. Directing autophagy to degrade cell surface receptors.
  28. ZLDI-8 facilitates pexophagy by ROS-mediated activation of TFEB and ATM in HeLa cells.
  29. Predicting Which Mitophagy Proteins Are Dysregulated in Spinocerebellar Ataxia Type 3 (SCA3) Using the Auto-p2docking Pipeline.
  30. Mitophagy and Its Significance in Periodontal Disease.
  31. Omega-3 PUFAs improve cognitive function in heat-stressed mice by enhancing autophagy via inhibition of the phosphorylation of the PI3K-Akt-mTOR pathway.
  32. Quality control of ABCD3 by the VCP-FAF2 complex suppresses excessive pexophagy.
  33. ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.
  34. Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.
  35. TMBIM1 ameliorates sepsis-induced cardiac dysfunction by promoting Parkin-mediated mitophagy.
  36. SESN1 negatively regulates STING1 to maintain innate immune homeostasis.
  37. Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve is a Therapeutic Strategy for Pancreatic Cancer.
  38. Lysosomal Fe2+ influx through the MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.
  39. Unraveling the Binding Mode of TSC2-Rheb through Protein Docking and Simulations.
  40. Listerin promotes α-synuclein degradation to alleviate Parkinson's disease through the ESCRT pathway.
  41. Sodium-glucose cotransporter 2 inhibitor empagliflozin enhances autophagy and reverses remodeling in hearts with large, old myocardial infarctions.
  42. Cyclodepsipeptides and Fatty Acid Lactones from the Freshwater-Derived Fungus, Talaromyces gwangjuensis, and Their Potential as Autophagy Activators.
  43. Autophagy-Activating Nanoautophagosome-Tethering Compounds for Targeted Protein Degradation Specifically in Tumor Cells.
  44. Neuropeptide S and its receptor aggravated asthma via TFEB dependent autophagy in bronchial epithelial cells.
  45. CRISPuRe-seq: pooled screening of barcoded ribonucleoprotein reporters reveals regulation of RNA polymerase III transcription by the integrated stress response via mTOR.
  46. Hypoxia-Induced Metabolic and Functional Changes in Oral CSCs: Implications for Stemness and Viability Modulation Through BNIP3-Driven Mitophagy.
  47. NLRP3 inflammasome promotes functional repair after spinal cord injury in mice by regulating autophagy and its mechanism.
  48. Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response.
  49. Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation.
  50. Rpl12 is a conserved ribophagy receptor.
  51. mTORC2 Regulates Actin Polymerization in Auditory Cells.
  52. A novel lncRNA enhances autophagy to suppress extracellular matrix via modulating TP53INP1 in human trabecular meshwork cells under oxidative stress.
  53. Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations.
  54. Melatonin Mitigates Acidosis-Induced Neuronal Damage by Up-Regulating Autophagy via the Transcription Factor EB.
  55. FBXO45 restricts HIV-1 replication by inducing SQSTM1/p62-mediated autophagic degradation of Tat.
  56. An mTOR paradox in sarcopenia via BCAA catabolism.
  57. Selective clearance of aberrant membrane proteins by TORC1-mediated micro-ER-phagy.
  1. Front Cell Dev Biol. 2025 ;13 1532050
    Mechanisms and roles of membrane-anchored ATG8s.
    Soo-Kyeong Lee, Sang-Won Park, Deok-Jin Jang, Jin-A Lee.
      Autophagy-related protein 8 (ATG8) family proteins, including LC3 and GABARAP subfamilies, are pivotal in canonical autophagy, driving autophagosome formation, cargo selection, and lysosomal fusion. However, recent studies have identified non-canonical roles for lipidated ATG8 in processes such as LC3-associated phagocytosis (LAP), LC3-associated endocytosis (LANDO), and lipidated ATG8-mediated secretory autophagy. These pathways expand ATG8's functional repertoire in immune regulation, membrane repair, and pathogen clearance, as ATG8 becomes conjugated to single-membrane structures (e.g., phagosomes and lysosomes). This review examines the molecular mechanisms of ATG8 lipidation, focusing on its selective conjugation to phosphatidylethanolamine (PE) in autophagy and phosphatidylserine (PS) in CASM. We highlight LIR-based probes and LC3/GABARAP-specific deconjugases as critical tools that allow precise tracking and manipulation of ATG8 in autophagic and non-autophagic contexts. These advancements hold therapeutic promise for treating autophagy-related diseases, including cancer and neurodegenerative disorders, by targeting ATG8-driven pathways that maintain cellular homeostasis.
    Keywords:  LAP; LC3/GABARAP; LIR motif; Lando; autophagy; deconjugase; non-canonical autophagy; probe
    DOI:  https://doi.org/10.3389/fcell.2025.1532050
  2. Front Cell Dev Biol. 2025 ;13 1518991
    Canonical and noncanonical autophagy: involvement in Parkinson's disease.
    Maria Sakurai, Tomoki Kuwahara.
      Autophagy is the major degradation process in cells and is involved in a variety of physiological and pathological functions. While macroautophagy, which employs a series of molecular cascades to form ATG8-coated double membrane autophagosomes for degradation, remains the well-known type of canonical autophagy, microautophagy and chaperon-mediated autophagy have also been characterized. On the other hand, recent studies have focused on the functions of autophagy proteins beyond intracellular degradation, including noncanonical autophagy, also known as the conjugation of ATG8 to single membranes (CASM), and autophagy-related extracellular secretion. In particular, CASM is unique in that it does not require autophagy upstream mechanisms, while the ATG8 conjugation system is involved in a manner different from canonical autophagy. There have been many reports on the involvement of these autophagy-related mechanisms in neurodegenerative diseases, with Parkinson's disease (PD) receiving particular attention because of the important roles of several causative and risk genes, including LRRK2. In this review, we will summarize and discuss the contributions of canonical and noncanonical autophagy to cellular functions, with a special focus on the pathogenesis of PD.
    Keywords:  CASM; LRRK2; Parkinson’s disease; autophagy-related secretion; lysosome; noncanonical autophagy; α-synuclein
    DOI:  https://doi.org/10.3389/fcell.2025.1518991
  3. Autophagy. 2025 Feb 12.
    Transcriptional repression of autophagy and lysosome biogenesis.
    Jaebeom Kim, Young Suk Yu, Keun Il Kim, Sung Hee Baek.
      The microphthalmia/transcription factor E (MiT/TFE) family activates macroautophagy/autophagy and lysosomal genes during acute nutrient deficiency. However, the mechanisms that suppress transcription of these genes under steady-state, nutrient-rich conditions to prevent unnecessary expression remain unclear. In this study, we identified a previously unrecognized mechanism of transcriptional repression for autophagy and lysosomal genes. Under nutrient-rich conditions, USF2 (upstream transcription factor 2) binds to the coordinated lysosomal expression and regulation (CLEAR) motif, recruiting a repressive complex containing HDAC (histone deacetylase). In contrast, during nutrient deficiency, TFEB (transcription factor EB) displaces USF2 at the same motif, activating transcription. This switch is regulated by USF2 phosphorylation at serine 155 by GSK3B (glycogen synthase kinase 3 beta). Reduced phosphorylation under nutrient-deprived conditions weakens USF2's DNA binding affinity, allowing TFEB to competitively bind and activate target genes. Knockdown or knockout of Usf2 upregulates specific autophagy and lysosomal genes, leading to enhanced lysosomal functionality and increased autophagic flux. In USF2-deficient cells, the SERPINA1 Z variant/antitrypsin Z - an aggregation-prone mutant protein used as a model - is rapidly cleared via the autophagy-lysosome pathway. Therefore, modulation of USF2 activity may be a therapeutic strategy for managing diseases associated with autophagy and lysosomal dysfunction.
    Keywords:  Autophagy; MiT/TFE; TFEB; USF2; lysosome; transcriptional repressor
    DOI:  https://doi.org/10.1080/15548627.2025.2465404
  4. Elife. 2025 Feb 12. pii: RP98523. [Epub ahead of print]13
    Ezrin defines TSC complex activation at endosomal compartments through EGFR-AKT signaling.
    Giuliana Giamundo, Daniela Intartaglia, Eugenio Del Prete, Elena Polishchuk, Fabrizio Andreone, Marzia Ognibene, Sara Buonocore, Bruno Hay Mele, Francesco Giuseppe Salierno, Jlenia Monfregola, Dario Antonini, Paolo Grumati, Alessandra Eva, Rossella De Cegli, Ivan Conte.
      Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane-actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.
    Keywords:  EGFR; EZRIN; TSC complex; cell biology; endosome; lysosome; mTORC1
    DOI:  https://doi.org/10.7554/eLife.98523
  5. Cell Mol Bioeng. 2025 Feb;18(1): 39-52
    Hyperosmotic Stress Promotes the Nuclear Translocation of TFEB in Tubular Epithelial Cells Depending on Intracellular Ca2+ Signals via TRPML Channels.
    Takashi Miyano, Atsushi Suzuki, Hisaaki Konta, Naoya Sakamoto.
       Purpose: We previously demonstrated that hyperosmotic stress, which acts as mechanical stress, induces autophagy of tubular epithelial cells. This study aims to elucidate the molecular mechanisms of hyperosmolarity-induced autophagy. The research question addresses how hyperosmotic stress activates autophagy through transcription factor EB (TFEB) and Ca2+ signaling pathways, contributing to understanding cellular responses to mechanical stress.
    Methods: NRK-52E normal rat kidney cells were subjected to hyperosmotic stress using mannitol-containing medium. Fluorescence microscopy was utilized to observe TFEB nuclear translocation, a crucial event in autophagy regulation. An intracellular Ca2+ chelator, BAPTA-AM, and a calcineurin inhibitor were used to dissect the Ca2+ signaling pathway involved in TFEB translocation. The phosphorylation of p70S6K, a substrate of the mammalian target of rapamycin complex 1 kinase, was analyzed to explore its role in TFEB localization. Additionally, the function of transient receptor potential mucolipin 1 (TRPML1), an intracellular Ca2+ channel, was assessed using pharmacological inhibition to determine its impact on TFEB translocation and autophagy marker LC3-II levels.
    Results: Mannitol-induced hyperosmotic stress promoted the nuclear translocation of TFEB, which was completely abolished by treatment with BAPTA-AM. Inhibition of calcineurin suppressed TFEB nuclear translocation under hyperosmolarity, indicating that a signaling pathway governed by intracellular Ca2+ is involved in TFEB's nuclear translocation. In contrast, hyperosmotic stress did not significantly alter p70S6K phosphorylation. Pharmacological inhibition of TRPML1 attenuated both TFEB nuclear translocation and LC3-II upregulation in response to hyperosmotic stress.
    Conclusions: Hyperosmotic stress promotes TFEB nuclear localization, and TRPML1-induced activation of calcineurin is involved in the mechanism of hyperosmolarity-induced autophagy.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00839-6.
    Keywords:  Calcineurin; Hyperosmolarity; TRPML1; Transcription factor EB (TFEB); Tubular epithelial cell
    DOI:  https://doi.org/10.1007/s12195-024-00839-6
  6. Brain Res. 2025 Feb 06. pii: S0006-8993(25)00052-6. [Epub ahead of print]1851 149494
    Advancements in autophagy perturbations in Alzheimer's disease: Molecular aspects and therapeutics.
    Rishika Dhapola, Sneha Kumari, Prajjwal Sharma, Balachandar Vellingiri, Dibbanti HariKrishnaReddy.
      Emerging evidences suggest that autophagy, a key cellular process responsible for degrading and recycling damaged organelles and proteins, plays a crucial role in maintaining neuronal health. Dysfunctional autophagy has been linked to the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of misfolded proteins and cellular debris. Molecular mechanisms underlying autophagy dysfunction in AD involve amyloid-beta (Aβ) and tau accumulation, neuroinflammation, mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress. Disrupted signaling pathways such as TRIB3, Nmnat and BAG3 that regulate key processes like autophagosome initiation, lysosome function, and protein homeostasis also play a crucial role in the pathogenesis. Restoration of autophagy by modulating these molecular and signaling pathways may be an effective therapeutic strategy for AD. Studies have found few drugs targeting autophagy dysregulation in AD. These drugs include metformin that has been found to modulate the expression of TRIB3 for autophagy regulation. Another drug, resveratrol has been reported to augment the activity of Nmnat thus, increases autophagy flux. BACE1 and mTOR inhibitors like arctigenin, nilvadipine and dapagliflozin were also found to restore autophagy. This study elaborates recent advances in signaling and molecular pathways and discusses current and emerging therapeutic interventions targeting autophagy dysfunction in AD.
    Keywords:  Alzheimer’s disease; Autophagy; Molecular pathways; Signaling pathways; Therapeutics
    DOI:  https://doi.org/10.1016/j.brainres.2025.149494
  7. Autophagy. 2025 Feb 12.
    Buddleoside alleviates nonalcoholic steatohepatitis by targeting the AMPK-TFEB signaling pathway.
    Meng Chen, Guowen Liu, Zhiyuan Fang, Wenwen Gao, Yuxiang Song, Lin Lei, Xiliang Du, Xinwei Li.
      Nonalcoholic steatohepatitis (NASH) is a combination of hepatic steatosis, inflammation, and fibrosis, and it often follows simple hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). However, no pharmacological treatment is currently available for NASH. Given the important role of TFEB (transcription factor EB) in regulating the macroautophagy/autophagy-lysosomal pathway, TFEB is potentially a novel therapeutic target for treatment of NASH, which function can be regulated by AMP-activated protein kinase (AMPK) and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Buddleoside (Bud), a natural flavonoid compound, has recently emerged as a promising drug candidate for liver diseases. Here, we shown that Bud treatment alleviated hepatic steatosis, insulin resistance, inflammation, and fibrosis in mice fed a high-fat and high-cholesterol (HFHC) diet. Notably, Bud activated AMPK, inhibited MTORC1, and enhanced TFEB transcriptional activity as well as autophagic flux in vivo and in vitro. Inhibition of AMPK or knockout of hepatic Tfeb abrogated the alleviation effects of Bud on hepatic steatosis, insulin resistance, inflammation, and fibrosis. Mechanistic investigation revealed that Bud bound to the PRKAB1 subunit via Val81, Arg83, and Ser108 residues and activated AMPK, thereby eliciting phosphorylation of RPTOR (regulatory associated protein of MTOR complex 1) and inhibiting the kinase MTORC1, which activated the TFEB-mediated autophagy-lysosomal pathway and further ameliorated HFHC-induced NASH in mice. Altogether, our results indicate that Bud ameliorates NASH by activating hepatic the AMPK-TFEB axis, suggesting that Bud is a potential therapeutic strategy for NASH.
    Keywords:  Autophagy; MTORC1; buddleoside; fatty liver; inflammation
    DOI:  https://doi.org/10.1080/15548627.2025.2466145
  8. J Cell Biol. 2025 Apr 07. pii: e202407105. [Epub ahead of print]224(4):
    The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux.
    Brian J North, Amelia E Ohnstad, Michael J Ragusa, Christopher J Shoemaker.
      During autophagy, toxic cargo is encapsulated by autophagosomes and trafficked to lysosomes for degradation. NBR1, an autophagy receptor targeting ubiquitinated aggregates, serves as a model for studying the multivalent, heterotypic interactions of cargo-bound receptors. Here, we find that three critical NBR1 partners-ATG8-family proteins, FIP200, and TAX1BP1-each bind to distinct, overlapping determinants within a short linear interaction motif (SLiM). To explore whether overlapping SLiMs extend beyond NBR1, we analyzed >100 LC3-interacting regions (LIRs), revealing that FIP200 and/or TAX1BP1 binding to LIRs is a common phenomenon and suggesting LIRs as protein interaction hotspots. Phosphomimetic peptides demonstrate that phosphorylation generally enhances FIP200 and ATG8-family binding but not TAX1BP1, indicating differential regulation. In vivo, LIR-mediated interactions with TAX1BP1 promote optimal NBR1 flux by leveraging additional functionalities from TAX1BP1. These findings reveal a one-to-many binding modality in the LIR motif of NBR1, illustrating the cooperative mechanisms of autophagy receptors and the regulatory potential of multifunctional SLiMs.
    DOI:  https://doi.org/10.1083/jcb.202407105
  9. Int J Mol Sci. 2025 Jan 30. pii: 1193. [Epub ahead of print]26(3):
    Retinal Pigment Epithelium Under Oxidative Stress: Chaperoning Autophagy and Beyond.
    Yuliya Markitantova, Vladimir Simirskii.
      The structural and functional integrity of the retinal pigment epithelium (RPE) plays a key role in the normal functioning of the visual system. RPE cells are characterized by an efficient system of photoreceptor outer segment phagocytosis, high metabolic activity, and risk of oxidative damage. RPE dysfunction is a common pathological feature in various retinal diseases. Dysregulation of RPE cell proteostasis and redox homeostasis is accompanied by increased reactive oxygen species generation during the impairment of phagocytosis, lysosomal and mitochondrial failure, and an accumulation of waste lipidic and protein aggregates. They are the inducers of RPE dysfunction and can trigger specific pathways of cell death. Autophagy serves as important mechanism in the endogenous defense system, controlling RPE homeostasis and survival under normal conditions and cellular responses under stress conditions through the degradation of intracellular components. Impairment of the autophagy process itself can result in cell death. In this review, we summarize the classical types of oxidative stress-induced autophagy in the RPE with an emphasis on autophagy mediated by molecular chaperones. Heat shock proteins, which represent hubs connecting the life supporting pathways of RPE cells, play a special role in these mechanisms. Regulation of oxidative stress-counteracting autophagy is an essential strategy for protecting the RPE against pathological damage when preventing retinal degenerative disease progression.
    Keywords:  autophagy; chaperone mediated autophagy; heat shock proteins; lysosomes; mitochondrial dysfunction; oxidative stress; phagocytosis; programmed cell death; proteostasis system; retinal pigment epithelium; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3390/ijms26031193
  10. Mol Brain. 2025 Feb 12. 18(1): 11
    Development of selective deconjugases for membrane-anchored LC3A/B in post-mitotic neurons.
    Haneul Choi, Sang-Won Park, Deok-Jin Jang, Jin-A Lee.
      Neuronal autophagy is essential for maintaining protein and organelle turnover, thereby safeguarding neuronal health. LC3, a central autophagy protein, exists in lipidated (LC3-II) and non-lipidated (LC3-I) forms, both critical for neurons due to their sensitivity to metabolic and proteostatic stress. To elucidate the specific roles of membrane-anchored LC3A/B in post-mitotic neurons, we engineered deconjugases with enhanced selectivity for lipidated LC3. By modifying LC3-interacting regions (LIRs) at the deconjugase termini, we significantly improved targeting specificity toward LC3A/B. Deconjugases with N-terminal LIR modifications reduced LC3A/B-associated autophagosomes, highlighting the importance of LIR positioning for specificity. Sequential N-terminal LIR arrangements further refined LC3A/B targeting without affecting GABARAP-associated autophagosomes. Moreover, reducing the hydrophobicity of the α3 helix to limit membrane residence time further improved selectivity. These targeted modifications demonstrate the potential of customized deconjugases to dissect and modulate specific autophagic pathways in neurons, paving the way for novel therapeutic strategies against neurodegenerative diseases associated with autophagy dysregulation.
    Keywords:  Deconjugases; LC3/GABARAP; Neuronal autophagy; RavZ
    DOI:  https://doi.org/10.1186/s13041-025-01184-z
  11. Autophagy. 2025 Feb 12.
    Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.
    Ning Ding, Yijie Song, Yuhang Zhang, Wei Yu, Xinnan Li, Wei Li, Lei Li.
      The CGG repeat expansions in the 5"-UTR regions of certain genes have been implicated in various neurodegenerative and muscular disorders. However, the underlying pathogenic mechanisms are not well understood. In this study, we explore the role of the small molecular chaperone HSPB1 in counteracting neurodegeneration induced by poly-glycine (poly-G) aggregates. Employing a reporter system, we demonstrate that CGG repeat expansions within the 5"-UTR of the GIPC1 gene produce poly-G proteins, by repeat-associated non-AUG (RAN) translation. Through proximity labeling and subsequent mass spectrometry analysis, we characterize the composition of poly-G insoluble aggregates and reveal that these aggregates sequester key macroautophagy/autophagy receptors, SQSTM1/p62 and TOLLIP. This sequestration disrupts MAP1LC3/LC3 recruitment and impairs autophagosome formation, thereby compromising the autophagic pathway. Importantly, we show that HSPB1 facilitates the dissociation of these receptors from poly-G aggregates and consequently restores autophagic function. Overexpressing HSPB1 alleviates poly-G-induced neurodegeneration in mouse models. Taken together, these findings highlight a mechanistic basis for the neuroprotective effects of HSPB1 and suggest its potential as a therapeutic target in treating poly-G-associated neurodegenerative diseases.
    Keywords:  Autophagy receptors; CGG repeat expansions; HSPB1; RAN translation; p62; poly-glycine
    DOI:  https://doi.org/10.1080/15548627.2025.2466144
  12. Cells. 2025 Jan 24. pii: 183. [Epub ahead of print]14(3):
    Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target.
    Zhengchao Wang, Xiang Li, Alexandra K Moura, Jenny Z Hu, Yun-Ting Wang, Yang Zhang.
      Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy-lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies.
    Keywords:  atherosclerosis; autophagy; endothelial cells; lysosomes; macrophages; smooth muscle cells
    DOI:  https://doi.org/10.3390/cells14030183
  13. Front Mol Biosci. 2024 ;11 1516789
    Aging, cancer, and autophagy: connections and therapeutic perspectives.
    Begoña Zapatería, Esperanza Arias.
      Aging and cancer are intricately linked through shared molecular processes that influence both the onset of malignancy and the progression of age-related decline. As organisms age, cellular stress, genomic instability, and an accumulation of senescent cells create a pro-inflammatory environment conducive to cancer development. Autophagy, a cellular process responsible for degrading and recycling damaged components, plays a pivotal role in this relationship. While autophagy acts as a tumor-suppressive mechanism by preventing the accumulation of damaged organelles and proteins, cancer cells often exploit it to survive under conditions of metabolic stress and treatment resistance. The interplay between aging, cancer, and autophagy reveals key insights into tumorigenesis, cellular senescence, and proteostasis dysfunction. This review explores the molecular connections between these processes, emphasizing the potential for autophagy-targeted therapies as strategies that could be further explored in both aging and cancer treatment. Understanding the dual roles of autophagy in suppressing and promoting cancer offers promising avenues for therapeutic interventions aimed at improving outcomes for elderly cancer patients while addressing age-related deterioration.
    Keywords:  aging; autopaghy; cancer; proteostasis; therapeutics
    DOI:  https://doi.org/10.3389/fmolb.2024.1516789
  14. Trends Cell Biol. 2025 Feb 07. pii: S0962-8924(25)00003-0. [Epub ahead of print]
    Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.
    Michael J Clague, Sylvie Urbé.
      The selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCFFBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.
    Keywords:  BNIP3; FBXL4; PINK1; PPTC7; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2025.01.003
  15. Dis Model Mech. 2025 Feb 01. pii: DMM052007. [Epub ahead of print]18(2):
    Transcriptional regulation of autophagy in skeletal muscle stem cells.
    Priya D Gopal Krishnan, Wen Xing Lee, Kah Yong Goh, Sze Mun Choy, Lewin Raymarc Roldan Turqueza, Zhuo Han Lim, Hong-Wen Tang.
      Muscle stem cells (MuSCs) are essential for the regenerative capabilities of skeletal muscles. MuSCs are maintained in a quiescent state, but, when activated, can undergo proliferation and differentiation into myocytes, which fuse and mature to generate muscle fibers. The maintenance of MuSC quiescence and MuSC activation are processes that are tightly regulated by autophagy, a conserved degradation system that removes unessential or dysfunctional cellular components via lysosomes. Both the upregulation and downregulation of autophagy have been linked to impaired muscle regeneration, causing myopathies such as cancer cachexia, sarcopenia and Duchenne muscular dystrophy. In this Review, we highlight the importance of autophagy in regulating MuSC activity during muscle regeneration. Additionally, we summarize recent studies that link the transcriptional dysregulation of autophagy to muscle atrophy, emphasizing the dominant roles that transcription factors play in myogenic programs. Deciphering and understanding the roles of these transcription factors in the regulation of autophagy during myogenesis could advance the development of regenerative medicine.
    Keywords:  Autophagy; Muscle diseases; Muscle regeneration; Muscle stem cells
    DOI:  https://doi.org/10.1242/dmm.052007
  16. Int J Mol Med. 2025 Apr;pii: 61. [Epub ahead of print]55(4):
    The role of autophagy in fibrosis: Mechanisms, progression and therapeutic potential (Review).
    Yongxin Chen, Zhuanghui Wang, Qinghong Ma, Chao Sun.
      Various forms of tissue damage can lead to fibrosis, an abnormal reparative reaction. In the industrialized countries, 45% of deaths are attributable to fibrotic disorders. Autophagy is a highly preserved process. Lysosomes break down organelles and cytoplasmic components during autophagy. The cytoplasm is cleared of pathogens and dysfunctional organelles, and its constituent components are recycled. With the growing body of research on autophagy, it is becoming clear that autophagy and its associated mechanisms may have a role in the development of numerous fibrotic disorders. However, a comprehensive understanding of autophagy in fibrosis is still lacking and the progression of fibrotic disease has not yet been thoroughly investigated in relation to autophagy‑associated processes. The present review focused on the latest findings and most comprehensive understanding of macrophage autophagy, endoplasmic reticulum stress‑mediated autophagy and autophagy‑mediated endothelial‑to‑mesenchymal transition in the initiation, progression and treatment of fibrosis. The article also discusses treatment strategies for fibrotic diseases and highlights recent developments in autophagy‑targeted therapies.
    Keywords:  autophagy; endoplasmic reticulum stress; endothelial mesenchymal transition; fibrosis; macrophage autophagy
    DOI:  https://doi.org/10.3892/ijmm.2025.5502
  17. Front Immunol. 2025 ;16 1504583
    Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity.
    Matthew C Austin, Charanya Muralidharan, Saptarshi Roy, Justin J Crowder, Jon D Piganelli, Amelia K Linnemann.
       Background: Type 1 Diabetes (T1D) is caused by a combination of genetic and environmental factors that trigger autoimmune-mediated destruction of pancreatic β-cells. Defects in β-cell stress response pathways such as autophagy may play an important role in activating and/or exacerbating the immune response in disease development. Previously, we discovered that β-cell autophagy is impaired prior to the onset of T1D, implicating this pathway in T1D pathogenesis.
    Aims: To assess the role of autophagy in β-cell health and survival, and whether defects in autophagy render islets more immunogenic.
    Methods: We knocked out the critical autophagy enzyme, ATG7, in the β-cells of mice (ATG7Δβ-cell) then monitored blood glucose, performed glucose tolerance tests, and evaluated bulk islet mRNA and protein. We also assessed MHC-I expression and presence of CD45+ immune cells in ATG7Δβ-cell islets and evaluated how impaired autophagy affects EndoC-βH1 HLA-I expression under basal and IFNα stimulated conditions. Lastly, we co-cultured ATG7Δβ-cell islet cells with diabetogenic BDC2.5 helper T cells and evaluated T cell activation.
    Results: We found that all ATG7Δβ-cell mice developed diabetes between 11-15 weeks of age. Gene ontology analysis revealed a significant upregulation of pathways involved in inflammatory processes, response to ER stress, and the ER-associated degradation pathway. Interestingly, we also observed upregulation of proteins involved in MHC-I presentation, suggesting that defective β-cell autophagy may alter the immunopeptidome, or antigen repertoire, and enhance β-cell immune visibility. In support of this hypothesis, we observed increased MHC-I expression and CD45+ immune cells in ATG7Δβ-cell islets. We also demonstrate that HLA-I is upregulated in EndoC β-cells when autophagic degradation is inhibited. This effect was observed under both basal and IFNα stimulated conditions. Conversely, a stimulator of lysosome acidification/function, C381, decreased HLA-I expression. Lastly, we showed that in the presence of islet cells with defective autophagy, there is enhanced BDC2.5 T cell activation.
    Conclusions: Our findings demonstrate that β-cell autophagy is critical to cell survival/function. Defective β-cell autophagy induces ER stress, alters pathways of antigen production, and enhances MHC-I/HLA-I presentation to surveilling immune cells. Overall, our results suggest that defects in autophagy make β-cells more susceptible to immune attack and destruction.
    Keywords:  HLA-I expression; autophagy; islet immunogenicity; type 1 diabetes; β-cell stress
    DOI:  https://doi.org/10.3389/fimmu.2025.1504583
  18. Mol Neurobiol. 2025 Feb 14.
    Microglial NLRP3 Inflammasomes in Alzheimer's Disease Pathogenesis: From Interaction with Autophagy/Mitophagy to Therapeutics.
    Gunel Ayyubova, Leelavathi N Madhu.
      The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.
    Keywords:  Alzheimer’s disease; Autophagy; Microglia; Mitophagy; NLRP3 inflammasome
    DOI:  https://doi.org/10.1007/s12035-025-04758-z
  19. Nucleic Acids Res. 2025 Feb 08. pii: gkaf074. [Epub ahead of print]53(4):
    NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome.
    Edilene Siqueira, Cecilia D Velasco, Ariadna Tarrasón, Marta Soler, Tara Srinivas, Fernando Setién, Cristina Oliveira-Mateos, Marta Casado-Pelaez, Laura Martinez-Verbo, Judith Armstrong, Manel Esteller, Letícia F Alves, Artur Llobet, Sonia Guil.
      Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by loss-of-function mutations in the MECP2 gene, resulting in diverse cellular dysfunctions. Here, we investigated the role of the long noncoding RNA (lncRNA) NEAT1 in the context of MeCP2 deficiency using human neural cells and RTT patient samples. Through single-cell RNA sequencing and molecular analyses, we found that NEAT1 is markedly downregulated in MECP2 knockout (KO) cells at various stages of neural differentiation. NEAT1 downregulation correlated with aberrant activation of the mTOR pathway, abnormal protein metabolism, and dysregulated autophagy, contributing to the accumulation of protein aggregates and impaired mitochondrial function. Reactivation of NEAT1 in MECP2-KO cells rescued these phenotypes, indicating its critical role downstream of MECP2. Furthermore, direct RNA-RNA interaction was revealed as the key process for NEAT1 influence on autophagy genes, leading to altered subcellular localization of specific autophagy-related messenger RNAs and impaired biogenesis of autophagic complexes. Importantly, NEAT1 restoration rescued the morphological defects observed in MECP2-KO neurons, highlighting its crucial role in neuronal maturation. Overall, our findings elucidate lncRNA NEAT1 as a key mediator of MeCP2 function, regulating essential pathways involved in protein metabolism, autophagy, and neuronal morphology.
    DOI:  https://doi.org/10.1093/nar/gkaf074
  20. Immunity. 2025 Feb 11. pii: S1074-7613(25)00037-8. [Epub ahead of print]58(2): 265-267
    Next generation lysosome: Brought to you by cGAS-STING.
    Lei Wang, Wen Zhou.
      Renowned for driving interferon responses, the cGAS-STING pathway reveals a surprising role: lysosomal biogenesis. In this issue of Immunity, Xu et al. uncover how STING activates the transcription factor TFEB, linking innate immune sensing to enhanced pathogen clearance through lysosomal activity.
    DOI:  https://doi.org/10.1016/j.immuni.2025.01.012
  21. Mol Nutr Food Res. 2025 Feb 13. e202400606
    The Yeast-Fermented Garlic and a Balance of Spermine/Spermidine Activates Autophagy via EGR1 Transcriptional Factor.
    Kun Xie, Satoshi Yano, Jinyun Wang, Shota Yamakoshi, Tomoe Ohta, Takuhiro Uto, Maiko Sakai, Xi He, Kaichi Yoshizaki, Takumi Kubota, Kohta Ohnishi, Taichi Hara.
      Spermine (SPM) and spermidine (SPD) are polyamines found in all organisms, and their concentrations can be regulated by ingestion. We demonstrated that yeast-fermented garlic (YF) extract significantly increased autophag flux in OUMS-36T-1 and HeLa cells expressing the fluorescent probe (GFP-LC3-RFP-LC3ΔG). YF-induced increase of autophagy occurred independently of mTORC1 signaling, and RNA-sequencing analysis revealed that EGR1 was the most significantly altered gene in YF-treated OUMS-36T-1 cells. YF-treated EGR1-deficient HAP1 cells displayed reduced autophagic flux (p < 0.05). YF-induced increasing of autophagic flux occurred via a specific SPM/SPD ratio. HAP1 cells treated with equivalent amounts of SPD or SPM as that found in YF did not increase autophagic flux (p > 0.05); however, treatment with SPD and SPM in the same ratio as that found in YF increased autophagic flux (p < 0.05). This specific SPM/SPD ratio reduced MG132-induced proteostress via EGR1-dependent pathways (p < 0.05). Thus, the SPM/SPD balance may regulate autophagy via EGR1-dependent pathways, and controlling this balance may provide a strategy to maintain cellular homeostasis.
    Keywords:  EGR1; autophagy; garlic; spermidine; spermine; transcriptome analysis
    DOI:  https://doi.org/10.1002/mnfr.202400606
  22. Stem Cell Rev Rep. 2025 Feb 12.
    FBXL4-Related Mitochondrial Depletion Syndrome Underscores the role of Mitophagy in Stem Cell Differentiation during Embryogenesis.
    Pankaj Prasun.
      FBXL4- related mitochondrial depletion syndrome is a very rare inherited disorder characterized by global developmental delays, hypotonia, seizures, growth failure, and early onset lactic acidosis. Often, it is associated with structural brain and heart defects, and facial dysmorphism suggesting an embryogenesis defect. FBXL4 encodes F-box and leucine-rich repeat protein 4 (FBXL4) which is involved in mitochondrial quality control and maintenance by regulating mitophagy. A recent study suggests that FBXL4 deficiency leads to increased mitophagy. Fine tuning of mitophagy is essential for stem cell differentiation during embryogenesis. The disruption of this process is the likely explanation of developmental defects in FBXL4- related mitochondrial depletion syndrome.
    Keywords:  Embryogenesis; FBXL4; Mitochondria; Mitophagy; Stem cell Differentiation
    DOI:  https://doi.org/10.1007/s12015-025-10854-3
  23. Cell Death Dis. 2025 Feb 12. 16(1): 89
    PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma.
    Toshinao Oyama, Caitlyn B Brashears, Richa Rathore, Heather Benect-Hamilton, Katharine E Caldwell, Naomi Dirckx, William G Hawkins, Brian A Van Tine.
      Osteosarcoma is a bone cancer that has been found to be metabolically dependent on the conversion of glucose to serine through the rate-limiting enzyme 3-phosphoglycerate dehydrogenase (PHGDH). The upregulation of PHGDH has been correlated with poor patient survival, and the inhibition of the serine synthesis pathway using targeted small-molecule inhibition of PHGDH induces a rapid metabolic adaptation that prevents cell death due to pro-survival signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway. Here, PHGDH inhibition in combination with mTORC1 signaling modulation for the treatment of osteosarcoma was evaluated. When combined with PHGDH inhibition, several non-rapalog inhibitors of mTORC1 activated Forkhead box O (FOXO) transcription factor 3 (FOXO3), a transcription factor associated with various cellular processes driving apoptosis. The activation of FOXO3 led to transcriptional activation of the pro-apoptotic gene p53 upregulated modulator of apoptosis (PUMA), inducing apoptosis when combined with PHGDH inhibition. These data suggest a path for the clinical development of PHGDH inhibitors in conjunction with mTORC1 pathway modulators in osteosarcoma.
    DOI:  https://doi.org/10.1038/s41419-025-07378-6
  24. Front Cell Dev Biol. 2024 ;12 1490902
    Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.
    Purva V Gade, Angela Victoria Rojas Rivera, Layla Hasanzadah, Sofie Strompf, Thomas Raymond Philipson, Matthew Gadziala, Atharva Tyagi, Arnav Bandam, Rithvik Gabbireddy, Fatah Kashanchi, Amanda Haymond, Lance A Liotta, Marissa A Howard.
      Mitophagy is a critically important survival mechanism in which toxic, aged, or defective mitochondria are segregated into mitophagosomes, which shuttle the damaged mitochondrial segments to the lysosome and proteasome for destruction. Cancer cells rely on mitophagy under conditions of high oxidative stress or increased energy demand. Oxidative stress can generate a large volume of damaged mitochondria, overwhelming lysosomal removal. Accumulated damaged mitochondria are toxic and their proper removal is crucial for maintaining mitochondrial health. We propose a new cancer cell mechanism for survival that is activated when the demand for segregating and eliminating damaged mitochondria exceeds the capacity of the lysosome or proteasome. Specifically, we show that tumor cells subjected to oxidative stress by carbonyl cyanide-3-chlorophenylhdrazone (CCCP) eliminate damaged mitochondria segments by bypassing the lysosome to export them outside the cell via extracellular vesicles (EVs), a process termed "secretory mitophagy". PINK1, the initiator of mitophagy, remains associated with the damaged mitochondria that exported in EVs. Using several types of cancer cells, we show that tumor cells treated with CCCP can be induced to switch over to secretory mitophagy by treatment with Bafilomycin A1, which blocks the fusion of mitophagosomes with lysosomes. Under these conditions, an increased number of PINK1 + EVs are exported. This is associated with greater cell survival by a given CCCP dose, enhanced mitochondrial ATP production, and reduced mitochondrial oxidative damage (membrane depolarization). Our data supports the hypothesis that secretory mitophagy is a previously unexplored process by which cancer cells adapt to survive therapeutic or hypoxic stress. Ultimately, our findings may inform new prevention strategies targeting pre-malignant lesions and therapeutic approaches designed to sensitize tumor cells to oxidative stress-inducing therapies.
    Keywords:  PINK1; cancer progression; cell survival; extracellular vesicles; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2024.1490902
  25. Cell Mol Life Sci. 2025 Feb 13. 82(1): 76
    Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.
    Flavien Picard, Takashi Nonaka, Edwige Belotti, Alexis Osseni, Elisabeth Errazuriz-Cerda, Coline Jost-Mousseau, Emilien Bernard, Agnès Conjard-Duplany, Delphine Bohl, Masato Hasegawa, Cédric Raoul, Thierry Galli, Laurent Schaeffer, Pascal Leblanc.
      Proteinopathies, such as amyotrophic lateral sclerosis (ALS), are marked by the accumulation of misfolded proteins that disrupt cellular processes. Eukaryotic cells have developed protein quality control systems to eliminate these aberrant proteins, but these systems often fail to differentiate between normal and misfolded proteins. In ALS, pathological inclusions primarily composed of misfolded TDP-43 are a hallmark of the disease. Recently, a novel unconventional secretion process called misfolding-associated protein secretion (MAPS) has been discovered to selectively export misfolded proteins. USP19, an Endoplasmic Reticulum-associated ubiquitin peptidase, plays a crucial role in this process. In this study, we investigated the impact of ER-anchored USP19 on the secretion of misfolded TDP-43. Here we found that USP19 overexpression significantly promotes the secretion of soluble and aggregated misfolded TDP-43, requiring both ER anchoring and ubiquitin peptidase activity. Characterization of the cellular and molecular mechanisms involved in this process highlighted the importance of early autophagosomal and late endosomal/amphisomal compartments, while lysosomes did not play a key role. By using dominant-negative mutants and small interfering RNAs, we identified that USP19-mediated secretion of misfolded TDP-43 is modulated by key factors involved in cellular trafficking and secretion pathways, such as ATG7, the ESCRT-O HGS/HRS, the Rab GTPases RAB11A, RAB8A, and RAB27A, and the v-SNARE VAMP7. We also confirmed the crucial role of the DNAJC5/CSPα cochaperone. Overall, this study provides new insights into how cells manage the secretion of misfolded TDP-43 proteins and potentially opens new avenues for therapeutic interventions in ALS and related disorders.
    Keywords:  ALS; Aggregates; Autophagosomes; Autophagy; Endosomes; Misfolding; Release/secretion; TDP-43; USP19; Ubiquitin peptidase
    DOI:  https://doi.org/10.1007/s00018-025-05589-w
  26. Sci Rep. 2025 Feb 12. 15(1): 5148
    Bafilomycin A1 induces colon cancer cell death through impairment of the endolysosome system dependent on iron.
    Dong Hwa Min, Dasom Kim, Seung Taek Hong, Joohee Kim, Min Jung Kim, Seung-Hae Kwon, Aeree Kim, Ji-Yun Lee.
      The late endolysosomal compartment plays a crucial role in cancer cell metabolism by regulating lysosomal activity, essential for cell proliferation, and the degradation of cellular components during the final stages of autophagy. Modulating late endolysosomal function represents a new target for cancer therapy. In this study, we investigated the effects of bafilomycin A1 (BA1), a vacuolar H+-ATPase inhibitor, on colon cancer and normal colon fibroblasts (CCD-18Co) cells. We found that very low concentrations (~ 2 nM) of BA1 selectively induced cell death in colon cancer cells. This cytotoxicity was associated with lysosomal stress response and dysregulation of iron homeostasis. BA1 treatment resulted in significant alterations to the endolysosomal system, including an increased number and size of lysosomes, lysosomal membrane permeabilization, and autophagy flux blockade. These changes were accompanied by endoplasmic reticulum stress and lipid droplet accumulation. Furthermore, BA1 decreased intracellular Fe2+ levels, as measured using FerroOrange. Notably, iron (III)-citrate supplementation rescued cells from BA1-induced death. These findings suggest that BA1-induced endolysosomal dysfunction impairs iron homeostasis, ultimately leading to colon cancer cell death. Our results highlight the potential of targeting endolysosomal function and iron homeostasis as novel therapeutic strategies for colon cancer, paving the way for more selective and effective treatments.
    Keywords:  Autophagy; Bafilomycin A1; Colorectal cancer; Endolysosome; Iron
    DOI:  https://doi.org/10.1038/s41598-025-89127-5
  27. Nat Rev Drug Discov. 2025 Feb 10.
    Directing autophagy to degrade cell surface receptors.
    M Teresa Villanueva.
      
    Keywords:  Biotechnology; Cancer; Chemical biology; Drug discovery
    DOI:  https://doi.org/10.1038/d41573-025-00026-w
  28. Bioorg Med Chem Lett. 2025 Feb 07. pii: S0960-894X(25)00039-3. [Epub ahead of print] 130130
    ZLDI-8 facilitates pexophagy by ROS-mediated activation of TFEB and ATM in HeLa cells.
    Yong Hwan Kim, Joon Bum Kim, Ji-Eun Bae, Na Yeon Park, Seong Hyun Kim, Daeun Park, Jun Hee So, Jae Man Lee, Kwiwan Jeong, Dong Kyu Choi, Doo Sin Jo, Dong-Hyung Cho.
      Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in ATG5-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by N-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.
    Keywords:  Peroxisome; Pexophagy; ROS; TFEB; ZLDI-8
    DOI:  https://doi.org/10.1016/j.bmcl.2025.130130
  29. Int J Mol Sci. 2025 Feb 04. pii: 1325. [Epub ahead of print]26(3):
    Predicting Which Mitophagy Proteins Are Dysregulated in Spinocerebellar Ataxia Type 3 (SCA3) Using the Auto-p2docking Pipeline.
    Jorge Vieira, Mariana Barros, Hugo López-Fernández, Daniel Glez-Peña, Alba Nogueira-Rodríguez, Cristina P Vieira.
      Dysfunctional mitochondria are present in many neurodegenerative diseases, such as spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). SCA3/MJD, the most frequent neurodegenerative ataxia worldwide, is caused by the abnormal expansion of the polyglutamine tract (polyQ) at ataxin-3. This protein is known to deubiquitinate key proteins such as Parkin, which is required for mitophagy. Ataxin-3 also interacts with Beclin1 (essential for initiating autophagosome formation adjacent to mitochondria), as well as with the mitochondrial cristae protein TBK1. To identify other proteins of the mitophagy pathway (according to the KEGG database) that can interact with ataxin-3, here we developed a pipeline for in silico analyses of protein-protein interactions (PPIs), called auto-p2docking. Containerized in Docker, auto-p2docking ensures reproducibility and reduces the number of errors through its simplified configuration. Its architecture consists of 22 modules, here used to develop 12 protocols but that can be specified according to user needs. In this work, we identify 45 mitophagy proteins as putative ataxin-3 interactors (53% are novel), using ataxin-3 interacting regions for validation. Furthermore, we predict that ataxin-3 interactors from both Parkin-independent and -dependent mechanisms are affected by the polyQ expansion.
    Keywords:  SCA3/MJD; in silico; mitophagy; pipeline
    DOI:  https://doi.org/10.3390/ijms26031325
  30. Oral Dis. 2025 Feb 10.
    Mitophagy and Its Significance in Periodontal Disease.
    Guliqihere Abulaiti, Xu Qin, Lili Chen, Guangxun Zhu.
       OBJECTIVES: Periodontal disease is a common chronic inflammatory condition affecting the tissues that support teeth, leading to their destruction. Mitophagy, a specialized form of autophagy responsible for degrading damaged mitochondria, plays a crucial role in maintaining cellular homeostasis. However, its role in periodontal disease progression remains poorly understood. This review aims to summarize recent research on mitophagy's role in periodontal disease pathogenesis.
    METHODS: A comprehensive literature review on mitophagy was conducted using PubMed, Scopus, and Web of Science databases, employing keywords related to periodontal disease such as "periodontal," "periodontitis," "gingiva," and "gingivitis."
    RESULTS: A review of 18 original studies revealed that mitophagy plays a crucial role in periodontal disease by regulating key pathophysiological mechanisms. Specifically, mitophagy modulates periodontal inflammation by influencing pro-inflammatory cytokines and mitochondrial reactive oxygen species. Additionally, it is essential for alveolar bone remodeling, impacting both bone resorption and regeneration. Mitophagy also regulates cell apoptosis within periodontal tissues, helping to preserve cellular function and tissue integrity during periodontal disease progression.
    CONCLUSIONS: Mitophagy regulates periodontal disease pathogenesis by modulating inflammation, bone remodeling, and cell death in periodontal tissues. Further research is needed to explore its therapeutic potential in periodontal disease treatment and improve targeted interventions.
    Keywords:  alveolar bone remodeling; apoptosis; inflammation; mitophagy; periodontal disease
    DOI:  https://doi.org/10.1111/odi.15279
  31. Food Funct. 2025 Feb 14.
    Omega-3 PUFAs improve cognitive function in heat-stressed mice by enhancing autophagy via inhibition of the phosphorylation of the PI3K-Akt-mTOR pathway.
    Zifu Ren, Mengyu Cai, Xinyao Liu, Xin Li, Wenjing Shi, Hongtao Lu, Hui Shen, Gen Miao, Qicheng Zhou, Hongxia Li.
      The adverse effects of elevated temperatures on human health are becoming progressively severe. This research established a mouse model of cognitive dysfunction induced by heat stress to examine the impact of omega-3 PUFAs on the cognitive capabilities of heat-stressed mice. The study also aimed to elucidate the role and potential mechanisms of autophagy regulation in cognitive enhancement through omega-3 PUFAs interventions. Administration of omega-3 PUFAs ameliorated cognitive deficits in heat-stressed mice and increased brain concentrations of these fatty acids. Notably, omega-3 PUFAs significantly protected hippocampal neurons' morphology, quantity, and synaptic architecture in heat-stressed mice. Additionally, omega-3 PUFAs intake reduced the prevalence of damaged mitochondria in the hippocampus and mitigated oxidative harm. Further investigation revealed that heat stress induces autophagy. However, the autophagic process becomes dysfunctional, leading to impaired autophagic activity. Omega-3 PUFAs supplementation markedly augmented hippocampal autophagy in the heat-stressed mice. Moreover, heat stress upregulated the phosphorylation of the PI3K-Akt-mTOR pathway in both the mouse hippocampus and HT22 cells. In contrast, omega-3 PUFAs intake significantly diminished the phosphorylation levels within this pathway, alleviating the autophagic fusion barrier imposed by heat stress and promoting autophagic flux. The findings suggest that omega-3 PUFAs supplementation during heat stress may bolster autophagic function by inhibiting the phosphorylation of the PI3K-Akt-mTOR pathway. This modulation reduces structural and oxidative stress damage, ultimately enhancing cognitive function in mice subjected to heat stress.
    DOI:  https://doi.org/10.1039/d4fo04107k
  32. Autophagy. 2025 Feb 10. 1-2
    Quality control of ABCD3 by the VCP-FAF2 complex suppresses excessive pexophagy.
    Fumika Koyano, Noriyuki Matsuda.
      Peroxisomes play many crucial roles in cells such as the oxidation of very long-chain fatty acids and the detoxification of hydrogen peroxide. Given that peroxisomes are constantly exposed to various stresses, it is reasonable to assume that peroxisomes undergo robust quality- and quantity-control. Although the molecular mechanisms of this control remain to be fully elucidated, we recently demonstrated that the VCP-FAF2 complex plays a pivotal role in peroxisomal maintenance. More specifically, we found that the complex prevents excessive selective autophagic peroxisomal degradation (pexophagy) by regulating the accumulation of the ubiquitinated form of peroxisomal membrane protein ABCD3.Abbreviation: ABCD3: ATP binding cassette subfamily D member 3, CALCOCO2: calcium binding and coiled-coil domain 2, FAF2: Fas associated factor family member 2, OPTN: optineurin, RB1CC1: RB1 inducible coiled-coil 1, SQSTM1: sequestosome 1, TAX1BP1: Tax1 binding protein 1, UBA domain: ubiquitin-associated domain, VCP: valosin containing protein.
    Keywords:  ABCD3; FAF2; VCP; peroxisome; pexophagy; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2025.2461473
  33. Autophagy. 2025 Feb 12.
    ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.
    Madhulika Tripathi, Karine Gauthier, Reddemma Sandireddy, Jin Zou, Priyanka Gupta, Suganya Sakthivel, Nah Jiemin, Kabilesh Arul, Keziah Tikno, Sung-Hee Park, Yajun Wu, Lijin Wang, Boon-Huat Bay, Lena Ho, Vincent Giguere, Sujoy Ghosh, Donald P McDonnell, Paul M Yen, Brijesh K Singh.
      Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, ESRRA (estrogen related receptor, alpha) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating Rplp1 (ribosomal protein lateral stalk subunit P1) gene expression. Overexpression or siRNA knockdown of Esrra in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome and macroautophagy/autophagy protein translation, and autophagy activity. Remarkably, we have found that ESRRA had dual functions by not only regulating transcription but also controlling adaptive translation via the ESRRA-RPLP1-lysosome-autophagy pathway during prolonged starvation.
    Keywords:  60S acidic ribosomal protein P1 (RPLP1); autophagy; estrogen related receptor alpha (ESRRA/ERRα); lysosome; starvation; translation
    DOI:  https://doi.org/10.1080/15548627.2025.2465183
  34. J Exp Med. 2025 Apr 07. pii: e20230173. [Epub ahead of print]222(4):
    Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.
    Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna.
      Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.
    DOI:  https://doi.org/10.1084/jem.20230173
  35. FASEB J. 2025 Feb 28. 39(4): e70397
    TMBIM1 ameliorates sepsis-induced cardiac dysfunction by promoting Parkin-mediated mitophagy.
    Weichang Huang, Anni Lou, Jun Wang, Yuegang Wang, Wenyong Zhang, Jierui Li, Shuanghu Wang, Shiyu Geng, Guozhen Wang, Xu Li.
      Myocardial dysfunction is a significant complication of sepsis that is associated with elevated mortality rates. Transmembrane BAX inhibitor motif containing 1 (TMBIM1), a stress-responsive protein, has garnered interest in the field of cardiovascular disease for its cardioprotective properties. Nevertheless, the role of TMBIM1 on sepsis-induced cardiac dysfunction (SICD) remains unknown. Here, our findings revealed a significant elevation in TMBIM1 expression within the myocardium following endotoxin challenge and further demonstrate the cardioprotective effects of TMBIM1 through adenovirus-mediated gene manipulation. Notably, lipopolysaccharide exposure markedly induced mitochondrial dysfunction in cardiomyocytes, which was effectively alleviated by TMBIM1 overexpression, while TMBIM1 knockdown exacerbated this dysfunction. Moreover, in cardiomyocytes subjected to endotoxin challenge, TMBIM1 was observed to interact with Parkin, facilitating its translocation from the cytosol to damaged mitochondria. This interaction enhanced the activation of mitophagy, thereby promoting the clearance of dysfunctional mitochondria and subsequently mitigating cellular injury. Hence, targeting TMBIM1 could be a novel therapeutic strategy for treating SICD.
    Keywords:  Parkin; TMBIM1; mitophagy; myocardial injury; sepsis
    DOI:  https://doi.org/10.1096/fj.202402599RR
  36. Autophagy. 2025 Feb 13. 1-18
    SESN1 negatively regulates STING1 to maintain innate immune homeostasis.
    Lingxiao Xu, Hongqian Zhang, Zuocheng Qiu, Shijing Wang, Chaoyang Wang, Hao Cheng, Qianya Wan, Mingyu Pan.
      STING1 is a central hub protein of CGAS-STING1 signaling which is important signaling axis to sense DNA for the host against pathogens infection through regulating type I interferon (IFN-I) production. However, excessive STING1 activation-induced overproduced IFN-I triggers tissue damage and autoimmune disorders. Thus, the activity of STING1 must be precisely regulated for immune homeostasis. Here, we discovered SESN1 (sestrin 1) as an essential negative regulator of STING1 to maintain immune homeostasis. Upon herpes simplex virus-1 (HSV-1) infection, the expression of SESN1 was downregulated, which enhanced potentiality to virus defense for host. Consistently, SESN1-deficient mice exhibited stronger ability against HSV-1 infection compared to wild-type littermates. Additionally, we found the expression of SESN1 was decreased in systemic lupus erythematosus (SLE) patients and trex1 KO mouse model of autoimmune disease. Intriguingly, the replenishment of SESN1 effectively impressed IFN-I production and autoimmune responses in the PBMCs of human SLE specimens and the trex1 KO mouse model both in vitro and in vivo. Mechanistically, SESN1 targeted STING1 and promoted STING1 autophagic degradation by facilitating the interaction of SQSTM1/p62 and STING1. Together, our study uncovers a crucial role of SESN1 for immune homeostasis to balance anti-virus and autoimmunity by regulating STING1. SESN1 might be a potential therapeutic target for infectious and autoimmune diseases.Abbreviations: BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HTDNA: herring testes DNA; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.
    Keywords:  Autophagy; Degradation; SESN1; STING1; immune homeostasis
    DOI:  https://doi.org/10.1080/15548627.2025.2463148
  37. Cancer Res. 2025 Feb 11.
    Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve is a Therapeutic Strategy for Pancreatic Cancer.
    Jonathan M DeLiberty, Mallory K Roach, Clint A Stalnecker, Ryan Robb, Elyse G Schechter, Noah L Pieper, Khalilah E Taylor, Lily M Pita, Runying Yang, Scott Bang, Kristina Drizyte-Miller, Sarah E Ackermann, Sheila R Nicewarner Peña, Elisa Baldelli, Sophia M Min, David H Drewry, Emanuel F Petricoin, John P Morris, Channing J Der, Adrienne D Cox, Kirsten L Bryant.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent growth. Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth. However, CQ is limited in terms of specificity and potency. To find alternative anti-autophagy strategies, here we performed a CRISPR-Cas9 loss-of-function screen in PDAC cell lines that identified the lipid kinase PIKfyve as a growth-promoting gene. PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment. PIKfyve inhibition caused lysosomal dysfunction, reduced autophagic flux, and led to the accumulation of autophagy-related proteins. Furthermore, PIKfyve inhibition blocked the compensatory increases in autophagic flux associated both with MEK inhibition and with direct RAS inhibition. Accordingly, combined inhibition of PIKfyve and the RAS-MAPK pathway showed robust growth suppression across a panel of KRAS-mutant PDAC models. Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1757
  38. Autophagy. 2025 Feb 12.
    Lysosomal Fe2+ influx through the MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.
    Meng-Meng Wang, Wuyang Wang, Jiansong Qi.
      Lysosomes are best known for their involvement in inflammatory responses, where they participate in the macroautophagy/autophagy process to eliminate inflammasomes. Recently, we have identified a previously overlooked function of lysosomes in regulating macrophage inflammatory responses. Specifically, lysosomes finely control the production of IL1B (interleukin 1 beta) by manipulating the release of lysosomal Fe2+ through MCOLN1. Mechanistically, reactive oxygen species (ROS), accumulated during sustained inflammation in macrophages, cause activation of the MCOLN1, a lysosomal cationic channel. The activation of MCOLN1 triggers the release of lysosomal Fe2 toward the cytosol, which in turn activates prolyl hydroxylase domain enzymes (PHDs). PHDs' activation represses the transcriptional regulator NFKB/NF-kB (nuclear factor kappa B) activity by restraining RELA/p65 in the cytosol, leading to decreased IL1B transcription in macrophages. Consequently, the property of controlling production and subsequent release of IL1B from macrophages allows the lysosome to finely restrict sustained inflammatory responses. These findings demonstrate that apart from relying on its degradative capability, the lysosome also limits excessive inflammatory responses to facilitate the restoration of cellular and tissue homeostasis in macrophages by modulating the release of lysosomal Fe2+ through MCOLN1. Even more, by suppressing IL1B production, in vivo stimulation of the MCOLN1 channel alleviates multiple clinical symptoms of dextran sulfate sodium (DSS)-induced colitis in mice, highlighting MCOLN1 as a promising therapeutic target for inflammatory bowel disease (IBD) in clinical settings.
    Keywords:  Lysosomes; MCOLN1; PHDs
    DOI:  https://doi.org/10.1080/15548627.2025.2465396
  39. Biochemistry. 2025 Feb 13.
    Unraveling the Binding Mode of TSC2-Rheb through Protein Docking and Simulations.
    Berith F Pape, Shraddha Parate, Leif A Eriksson, Vibhu Jha.
      Proteasome inhibitors (PIs) constitute the first line of therapy for multiple myeloma (MM). Despite the impressive clinical efficacy, MM remains fatal due to the development of drug resistance over time. During MM progression, stress responses to hypoxia and PIs suppress mammalian target of rapamycin complex 1 (mTORC1) activity by releasing tuberous sclerosis complex 2 (TSC2), which deactivates Ras homologue enriched in brain (Rheb), a crucial regulator of mTORC1. The efficacy of PIs targeting MM is enhanced when mTORC1 is hyperactivated. We thus propose that the inhibition of TSC2 will improve the efficacy of PIs targeting MM. To the best of our knowledge, no cocrystallized structure of the TSC2-Rheb complex has been reported. We therefore developed a representative model using the individual structures of TSC2 (PDB: 7DL2) and Rheb (PDB: 1XTS). Computational modeling involving an extensive protein-protein docking consensus approach was performed to determine the putative binding mode of TSC2-Rheb. The proposed docking poses were refined, clustered, and evaluated by MD simulations to explore the conformational dynamics and protein mobility, particularly at the drug-binding interface of TSC2-Rheb. Our results agree with the suggested binding mode of TSC2-Rheb previously reported in the literature. The results reported herein establish a basis for the development of new inhibitors blocking the binding of TSC2 and Rheb, aiming to reinstate mTORC1 activation and facilitate improved efficacy of PIs against multiple myeloma.
    DOI:  https://doi.org/10.1021/acs.biochem.4c00562
  40. Sci Adv. 2025 Feb 14. 11(7): eadp3672
    Listerin promotes α-synuclein degradation to alleviate Parkinson's disease through the ESCRT pathway.
    Fei Qin, Runyu Cao, Wenjing Cui, Xuemei Bai, Jiahua Yuan, Yuling Zhang, Yaxing Liu, Nan Cao, Na Dong, Min Zhou, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Bingyu Liu, Chengjiang Gao.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of abnormal α-synuclein (α-syn) within dopaminergic neurons in the substantia nigra region of the brain. Despite excessive accumulation of α-syn being key to the pathogenesis of PD, the mechanisms governing its clearance remain elusive. In this study, we found that the endosomal sorting complex required for transport (ESCRT) system plays a crucial role in capturing and facilitating the degradation of ubiquitinated α-syn. The E3 ubiquitin ligase Listerin was found to promote K27-linked polyubiquitination of α-syn, directing it to the endosome for subsequent degradation. We showed that the deletion of the Listerin gene exacerbates the neurodegenerative progression in a mouse model of PD, whereas the overexpression of Listerin effectively mitigates disease progression in PD mice. Consequently, our study reveals a mechanism for α-syn degradation and identifies Listerin as a promising therapeutic target for the treatment of PD.
    DOI:  https://doi.org/10.1126/sciadv.adp3672
  41. Eur J Pharmacol. 2025 Feb 06. pii: S0014-2999(25)00108-6. [Epub ahead of print]992 177355
    Sodium-glucose cotransporter 2 inhibitor empagliflozin enhances autophagy and reverses remodeling in hearts with large, old myocardial infarctions.
    Susumu Endo, Hiromitsu Kanamori, Akihiro Yoshida, Genki Naruse, Shingo Komura, Shingo Minatoguchi, Takatomo Watanabe, Tomonori Kawaguchi, Yoshihisa Yamada, Atsushi Mikami, Tatsuhiko Miyazaki, Haruhiko Akiyama, Hiroyuki Okura.
      Large clinical trials recently showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve the prognosis of heart failure patients with or without diabetes. Using a mouse model of large myocardial infarction, we investigated the therapeutic effects and underlying molecular mechanisms of the highly selective SGLT2 inhibitor empagliflozin in heart failure. Four weeks after myocardial infarction induced by left coronary artery ligation, the surviving mice were assigned to vehicle or empagliflozin groups and treated for 8 weeks. Empagliflozin did not alter body weight, blood pressure, glycohemoglobin, blood glucose or beta-hydroxybutyrate levels but significantly attenuated cardiac dysfunction and left ventricular dilatation (remodeling). Hearts from empagliflozin-treated mice showed less fibrosis, less cardiomyocyte hypertrophy, and lower myocardial ANP levels than those from vehicle-treated mice. Autophagy was augmented in cardiomyocytes from empagliflozin-treated mice, as indicated by increased myocardial microtubule-associated protein-1 LC3 (light chain 3)-II levels and LC-3-II/I ratio as well as increased levels of cathepsin D and ATP. Additionally, numerous autophagic vacuoles and lysosomes were observed, accompanied by increased AMP-activated protein kinase (AMPK) phosphorylation and suppression of mammalian target of rapamycin phosphorylation. Myocardial sodium-hydrogen antiporter (NHE)-1 expression was increased in infarcted mice, and that effect was unchanged by empagliflozin. In vitro, empagliflozin increased autophagic flux and induced an intracellular pH drop, AMPK activation and ATP production in cardiomyocytes. These effects were similar to those of the NHE-1 inhibitor cariporide, suggesting a possibility that they both act on the same pathway. Empagliflozin is a beneficial pharmacological tool that enhances autophagy to reverse remodeling in the postinfarction heart.
    Keywords:  AMPK; Autophagy; Heart failure; Myocardial infarction; NHE-1; Remodeling; SGLT2 inhibitor
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177355
  42. J Nat Prod. 2025 Feb 12.
    Cyclodepsipeptides and Fatty Acid Lactones from the Freshwater-Derived Fungus, Talaromyces gwangjuensis, and Their Potential as Autophagy Activators.
    Van-Hieu Mai, Seri Choi, Jorge-Eduardo Ponce-Zea, Thuong T T Nguyen, Hyung-Sik Kang, Heejung Yang, Hyang Burm Lee, Won-Keun Oh.
      Autophagy is a primary cellular mechanism that entails the degradation and recycling of impaired or redundant cellular constituents. It plays an essential role in maintaining cellular health and homeostasis. Dysfunction in autophagy has been implicated in a wide range of diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases. A total of 200 fungal extracts were screened for their ability to modulate autophagy in HEK293A cells, a human kidney cell line stably expressing GFP-tagged LC3, a marker of autophagy. A potential autophagy regulator extract was identified from the freshwater-derived fungus, Talaromyces gwangjuensis. Through the implementation of Feature-Based Molecular Networking (FBMN), seven cyclodepsipeptides (1-7) and four lactone derivatives (8-11) were isolated from the bioactive fractions. The chemical structure of the newly isolated compounds, arthrichitins E-H (1-4) and gwangjupones A-D (8-11), were elucidated using 1D and 2D NMR spectroscopy, Marfey's analysis, J-based configuration analysis, ECD, and DP4+ probability calculations. Compounds 1, 4, and 6 were found to stimulate autophagic flux in IMR90 cells infected with an adeno-associated virus carrying an mCherry-GFP-LC3 construct, highlighting their potential as autophagy activators.
    DOI:  https://doi.org/10.1021/acs.jnatprod.4c01172
  43. ACS Macro Lett. 2025 Feb 11. 250-257
    Autophagy-Activating Nanoautophagosome-Tethering Compounds for Targeted Protein Degradation Specifically in Tumor Cells.
    Mengchen Xu, Jiajing Chen, Shuyu Wang, Linlin Xu, Xiaohui Wu, Jinpu Yu, Feihe Ma, Linqi Shi.
      Autophagosome-tethering compounds (ATTECs) represent an emerging targeted protein degradation (TPD) technology that directly draws intracellular proteins of interest (POIs) into autolysosomes. Although ATTECs are currently dominated by small molecules, the poor cell-type specificity and pharmacokinetic profile limit their applications in certain diseases. Moreover, the suboptimal intrinsic autophagic activity of cells affects the ATTECs-mediated degradation capability. Here we develop a nano-ATTEC system using our unique mixed-shell polymeric micelle (MSPM)-based nanoplatform for tumor-specific degradation of POIs. We demonstrate that the MSPMs-based nano-ATTEC is efficiently taken up by tumor cells in the acidic tumor microenvironment and to degrade POIs, rather than by normal cells under physiological conditions. More importantly, we find that this nano-ATTEC can not only target autolysosomes but also robustly enhance the autophagy activity, thereby establishing a positive feedback mechanism based on the autophagy pathway for efficient degradation of POIs. We believe that this MSPMs-based nano-ATTEC will find broad applications in tumor therapy.
    DOI:  https://doi.org/10.1021/acsmacrolett.4c00789
  44. Respir Res. 2025 Feb 10. 26(1): 50
    Neuropeptide S and its receptor aggravated asthma via TFEB dependent autophagy in bronchial epithelial cells.
    Zhixu Wang, Peng Zhao, Gen Yan, Aijuan Sun, Li Xu, Jiao Li, Xiaorun Zhai, Xiangcen Liu, Tingting Mei, Yinghua Xuan, Yunjuan Nie.
       BACKGROUND: Asthma is a prevalent respiratory disorder with limited treatment strategy. Neuropeptide S (NPS) is a highly conserved peptide via binding to its receptor NPSR, a susceptibility gene for asthma from genomics studies. However, little is known about the role of NPS-NPSR in the pathogenesis of asthma. This study was performed to determine the effect and underlying mechanism of NPS-NPSR on asthma.
    METHODS: NPSR knockdown was verified to affect asthma through autophagy by transcriptome sequencing and molecular biology experiments in animal models. Silencing of transcription factor EB in a bronchial epithelial cell line and validation of NPS-NPSR activation of autophagy dependent on transcription factor EB.
    RESULTS: Our results showed that NPSR expression was markedly increased in asthmatic humans and mice, mainly localized in bronchial epithelial cells. Using ovalbumin (OVA) and papain-induced asthma mouse models, NPSR-deficient mice exhibited significantly alleviated asthma, with reduced small airway lesions and inflammatory infiltration compared with wild-type mice. OVA and papain promoted TFEB-mediated autophagy with increased ATG5 and LC3 II expression, and NPS effectively regulated the activation of TFEB and autophagy. In turn, specific TFEB knockdown could restore the effect of exogenous NPS and its receptor antagonist on the autophagy and cytokines secretion in bronchial epithelial cells. Furthermore, Prkcg may be the key upstream targeting of the TFEB-autophagy pathway involved in asthma.
    CONCLUSIONS: NPS-NPSR exacerbated asthma by regulating the TFEB-autophagy axis in airway epithelial injury, which may be a potential target for asthma therapy.
    Keywords:  Asthma; Autophagy; Bronchial epithelial cell; Neuropeptide S; TFEB
    DOI:  https://doi.org/10.1186/s12931-025-03125-9
  45. Nucleic Acids Res. 2025 Feb 08. pii: gkaf062. [Epub ahead of print]53(4):
    CRISPuRe-seq: pooled screening of barcoded ribonucleoprotein reporters reveals regulation of RNA polymerase III transcription by the integrated stress response via mTOR.
    David T Harris, Calvin H Jan.
      Genetic screens using CRISPR (Clustered Regularly Interspaced Palindromic Repeats) provide valuable information about gene function. Nearly all pooled screening technologies rely on the cell to link genotype to phenotype, making it challenging to assay mechanistically informative, biochemically defined phenotypes. Here, we present CRISPuRe-seq (CRISPR PuRification), a novel pooled screening strategy that expands the universe of accessible phenotypes through the purification of ribonucleoprotein complexes that link genotypes to expressed RNA barcodes. While screening for regulators of the integrated stress response (ISR), we serendipitously discovered that the ISR represses transfer RNA (tRNA) production under conditions of reduced protein synthesis. This regulation is mediated through inhibition of mTORC1 and corresponding activation of the RNA polymerase III inhibitor MAF1. These data demonstrate that coherent downregulation of tRNA expression and protein synthesis is achieved through cross-talk between the ISR and mTOR, two master integrators of cell state.
    DOI:  https://doi.org/10.1093/nar/gkaf062
  46. J Cell Mol Med. 2025 Feb;29(3): e70400
    Hypoxia-Induced Metabolic and Functional Changes in Oral CSCs: Implications for Stemness and Viability Modulation Through BNIP3-Driven Mitophagy.
    Xin Li, Hitesh Singh Chaouhan, Shao-Hua Yu, I-Kuan Wang, Tung-Min Yu, Ya-Wen Chuang, Kuen-Bao Chen, Feng-Yen Lin, Michael Yuan-Chien Chen, Che-Hao Hsu, Kuo-Ting Sun, Chi-Yuan Li.
      Oral squamous cell carcinomas (OSCCs), like several solid tumours, contain heterogeneous subpopulations of a small subset of cancer cells, termed cancer stem cells (CSCs), that are highly relevant to cancer metastasis and invasive properties. CSCs have also shown a high capacity to survive against various stressful environments, such as hypoxia. However, the molecular underpinnings behind the high potential of CSCs to survive under this stress remain unclear. The current study aimed to investigate the significance of autophagy systems in oral CSC maintenance and survival under stress conditions. Human OSCC cell lines OECM-1 and OECM-1 CSCs were cultured in different hypoxic time periods for proliferation and cytotoxicity analyses. The stemness property of CSCs is evaluated by sphere formation, transwell and wound healing assays protein expression of stemness, and epithelial-to-mesenchymal transition markers. Mitochondrial functions, including mitochondrial ROS generation, mitochondria dynamics, mitophagy, and mitochondrial metabolism (glycolysis and oxidative phosphorylation [OXPHOS]) were examined by western blotting, immunohistochemistry, and XF-seahorse assays, respectively. Under hypoxia, oral CSCs showed a higher proliferation rate with increased invasion/migration/EMT properties than OECM-1 cells. Further, hypoxia-induced BNIP3-driven mitophagy was activated in OECM-1 CSCs than in OECM-1 cells, which also triggered a metabolic shift towards OXPHOS, and BNIP3/-L silencing by siRNA significantly attenuated OECM-1 CSCs stemness features. TCGA data analyses also revealed a higher BNIP3 expression in head and neck squamous carcinoma patients' tumour samples associated with lower patient survival. Collectively, our results revealed a BNIP3/-L-driven autophagy contributes to the OECM-1 CSCs stemness features under hypoxia, suggesting a novel therapeutic strategy involving BNIP3 and autophagy inhibition in oral CSCs.
    Keywords:  BNIP3/‐L; Mitophagy; autophagy; cancer stem cells; oral squamous cell carcinoma; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/jcmm.70400
  47. Int Immunopharmacol. 2025 Feb 07. pii: S1567-5769(25)00220-6. [Epub ahead of print]149 114230
    NLRP3 inflammasome promotes functional repair after spinal cord injury in mice by regulating autophagy and its mechanism.
    Haozhe Tian, Juan Zheng, Fangli Wang, Wenjing Zhang, Yuqing Chen, Xiangshu Wang, Xiaoxuan Wang, Jin Xi, Jianguo Hu, Yuxin Zhang.
       BACKGROUND: Inflammation at the injury site exacerbates tissue cell death following a spinal cord injury (SCI). Studies show that NLRP3 inflammasomes are crucial in the inflammation following Spinal Cord Injury, and NLRP3 inflammasomes have been shown to promote cells to undergo excessive autophagy in other diseases. Moreover, excessive autophagy levels could hinder functional repair post-SCI. In this regard, we hypothesized that inhibiting NLRP3 inflammasomes could reduce autophagy levels at the injury site, thus promoting functional repair post-SCI.
    METHODS: Herein, a mouse SCI model was used for in vivo experiments, and an in vitro neuroinflammatory model created using LPS-activated BV2 cells was used for in vitro experiments. Histopathological staining was used to assess tissue repair. Western Blot (WB) and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) were used to detect changes in relevant autophagy molecules, macrophage polarization-related markers and downstream inflammatory factors, and Immunofluorescence (IF) was used to detect changes in macrophage polarization.
    RESULTS: Following SCI, the inhibition of NLRP3 inflammasomes resulting from intraperitoneal injection of MCC950 significantly reduced autophagy levels at the injury site, resulting in both histological and behavioral improvements. In addition, the phosphorylation of mTOR during inhibition of NLRP3 inflammasomes to reduce autophagy levels further improved the immune microenvironment at the injury site, and M2-type macrophages were significantly upregulated M2-type macrophages. Moreover, in vitro experiments yielded results consistent with those of in vivo experiments regarding changes in autophagy-related indexes and polarization-related markers.
    CONCLUSIONS: Inhibition of NLRP3 inflammasomes can reduce autophagy level at the injury site to promote functional recovery and play a neuroprotective role. Moreover, phosphorylation of mTOR during the process of inhibition of NLRP3 inflammasomes to reduce autophagy, leading to reduced autophagy levels, could improve the immune microenvironment at the injury site, thus promoting functional recovery and histopathological repair post-SCI.
    Keywords:  Autophagy; Macrophage polarization; NLRP3 Inflammasomes; Spinal Cord Injury; mTOR
    DOI:  https://doi.org/10.1016/j.intimp.2025.114230
  48. Cells. 2025 Jan 28. pii: 192. [Epub ahead of print]14(3):
    Chronic IL-1-Exposed LNCaP Cells Evolve High Basal p62-KEAP1 Complex Accumulation and NRF2/KEAP1-Dependent and -Independent Hypersensitive Nutrient Deprivation Response.
    Haley Dahl-Wilkie, Jessica Gomez, Anastasia Kelley, Kirti Manjit, Basir Mansoor, Preethi Kanumuri, Sammy Pardo, Dana Molleur, Rafah Falah, Anisha R Konakalla, Morolake Omiyale, Susan Weintraub, Nikki A Delk.
      Chronic inflammation is a cancer hallmark and chronic exposure to interleukin-1 (IL-1) transforms castration-sensitive prostate cancer (PCa) cells into more fit castration-insensitive PCa cells. p62 is a scaffold protein that protects cells from nutrient deprivation via autophagy and from cytotoxic reactive oxygen via NFκB and NRF2 antioxidant signaling. Herein, we report that the LNCaP PCa cell line acquires high basal accumulation of the p62-KEAP1 complex when chronically exposed to IL-1. p62 promotes non-canonical NRF2 antioxidant signaling by binding and sequestering KEAP1 to the autophagosome for degradation. But despite high basal p62-KEAP1 accumulation, only two of several NRF2-induced genes analyzed, GCLC and HMOX1, showed high basal mRNA levels, suggesting that the high basal p62-KEAP1 accumulation does not result in overall high basal NRF2 activity. Nutrient starvation induces NRF2-dependent GCLC upregulation and HMOX1 repression, and we found that chronic IL-1-exposed LNCaP cells show hypersensitivity to serum starvation-induced GCLC and HMOX1 regulation. Thus, chronic IL-1 exposure affects cell response to nutrient stress. While HMOX1 expression remains NRF2/KEAP1-dependent in chronic IL-1-exposed LNCaP cells, GCLC expression is NRF2/KEAP1-independent. Furthermore, the high basal p62-KEAP1 complex accumulation is not required to regulate GCLC or HMOX1 expression, suggesting cells chronically exposed to IL-1 evolve a novel NRF2-independent role for the p62/KEAP1 axis.
    Keywords:  GCLC; HMOX1; NRF2; chronic IL-1; p62-KEAP1
    DOI:  https://doi.org/10.3390/cells14030192
  49. Front Pharmacol. 2024 ;15 1496380
    Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation.
    Ai-Li Xu, Zheng Shen, Shi-Hao Wang, Hai-Yun Luan, Yong Xu, Ze-Chun Kang, Zi-Qi Liao, Jie Liu, Xiao-Lei Duan, Wei-Hua Bian, Hui Sun, Xin Xie.
      Doxorubicin (DOX) is a prevalent chemotherapeutic drug for treating several malignancies. However, the mechanisms of DOX induced cardiac toxicity is not fully understood. Previous studies have demonstrated that autophagy activation is essential in DOX-induced cardiac toxicity. Nevertheless, studies on the role of autophagy protein 5 (ATG5) in DOX-induced cardiac toxicity remain limited. Therefore, this study aimed to investigate the role of ATG5 in DOX-induced cardiac toxicity. Mice were intravenously administered DOX (5 mg/kg) for 4 weeks to establish a cardiac toxicity model. Heart function was determined using echocardiography, and cardiac tissue was assessed for protein expression, mRNA levels, fibrosis, and immunofluorescent staining. DOX treatment upregulated autophagy-related gene expression but inhibited autophagic flux in vitro and in vivo. DOX-treated mice exhibited decreased heart function and cardiomyocyte size and increased cardiac fibrosis, oxidative stress, and apoptosis. These effects of DOX were partially alleviated by rAAV9 expressing shRNA-ATG5 and deteriorated by rAAV9-ATG5. We demonstrated that genetic ATG5 knockdown or autophagy inhibition by chemical inhibitors increased GATA4 protein expression, which was reduced by ATG5 overexpression or autophagy activator in vitro and in vivo, suggesting that ATG5-mediated autophagy promoted GATA4 degradation. Moreover, enforced GATA4 re-expression significantly counteracted the toxic effects of ATG5 on DOX-treated hearts. In conclusion, our study demonstrated that manipulating ATG5 expression to regulate GATA4 degradation in the heart may be a promising approach for DOX-induced cardiac toxicity.
    Keywords:  Atg5; autophagy; cardiac toxicity; doxorubicin; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2024.1496380
  50. Nat Cell Biol. 2025 Feb 11.
    Rpl12 is a conserved ribophagy receptor.
    Yuting Chen, Jiaxin Hu, Pengwei Zhao, Jie Fang, Yingqi Kuang, Zhaojie Liu, Shuling Dong, Weijing Yao, Yuanyuan Ding, Xinhui Wang, Yibin Pan, Jianbin Wu, Jingwei Zhao, Jing Yang, Zhenzhong Xu, Xiaodi Liu, Yi Zhang, Choufei Wu, Liqin Zhang, Mingzhu Fan, Shan Feng, Zhi Hong, Zhangming Yan, Hongguang Xia, Kaiyue Tang, Bing Yang, Wei Liu, Qiming Sun, Kunrong Mei, Wei Zou, Yunpeng Huang, Du Feng, Cong Yi.
      Ribophagy is a selective autophagic process that regulates ribosome turnover. Although NUFIP1 has been identified as a mammalian receptor for ribophagy, its homologues do not exist in yeast and nematodes. Here we demonstrate that Rpl12, a ribosomal large subunit protein, functions as a conserved ribophagy receptor in multiple organisms. Disruption of Rpl12-Atg8s binding leads to significant accumulation of ribosomal proteins and rRNA, while Atg1-mediated Rpl12 phosphorylation enhances its association with Atg11, thus triggering ribophagy during starvation. Ribophagy deficiency accelerates cell death induced by starvation and pathogen infection, leading to impaired growth and development and a shortened lifespan in both Caenorhabditis elegans and Drosophila melanogaster. Moreover, ribophagy deficiency results in motor impairments associated with ageing, while the overexpression of RPL12 significantly improves movement defects induced by starvation, ageing and Aβ accumulation in fly models. Our findings suggest that Rpl12 functions as a conserved ribophagy receptor vital for ribosome metabolism and cellular homeostasis.
    DOI:  https://doi.org/10.1038/s41556-024-01598-2
  51. J Neurochem. 2025 Feb;169(2): e70012
    mTORC2 Regulates Actin Polymerization in Auditory Cells.
    Michael Lanz, Maurizio Cortada, Yu Lu, Soledad Levano, Daniel Bodmer.
      Mammalian target of rapamycin complex 2 (mTORC2) is essential for hearing by regulating auditory hair cell structure and function. However, mechanistic details of how mTORC2 regulates intracellular processes in sensory hair cells have not yet been clarified. To further elucidate the role of mTORC2 in auditory cells, we generated a Rictor knockout cell line from HEI-OC1 auditory cells. mTORC2-deficient auditory cells exhibited significant alterations in actin cytoskeleton morphology and decreased proliferation rates. Additionally, we observed a reduction in phosphorylation of protein kinase C alpha (PKCα) and disrupted actin polymerization in mTORC2-deficient cells. Using proteomics, we found that mTORC2 disruption altered expression of cytoskeleton-related proteins in auditory cells. These findings provide valuable mechanistic insights into the functional role of mTORC2 in auditory cells, potentially opening new perspectives to address sensorineural hearing loss.
    Keywords:  HEI‐OC1; Rictor; actin cytoskeleton; hair cell; mTORC2
    DOI:  https://doi.org/10.1111/jnc.70012
  52. Sci Rep. 2025 Feb 11. 15(1): 5049
    A novel lncRNA enhances autophagy to suppress extracellular matrix via modulating TP53INP1 in human trabecular meshwork cells under oxidative stress.
    Jinjun Tie, Junhong Guo, Yijia Huang, Zihan Huang, Zhichao Yan, Jiemei Yuan, Xiaoli Shen, Jiantao Wang.
      Primary open-angle glaucoma (POAG) can result in irreversible blindness. As an important etiological factor, oxidative stress can elicit extraordinary increase of extracellular matrix (ECM) in trabecular meshwork-schlemm canal, to increase aqueous humor outflow resistance and elevate intraocular pressure. Although autophagy plays an important role in clearing ECM, the functions of long non-coding RNAs (lncRNAs) in autophagy induced by oxidative stress in human trabecular meshwork cells (HTMCs) remain unclear. In our study, oxidative stress induced the expression of ECM and autophagy in TMCs after H2O2 treatment. Meanwhile, a novel lncRNA ENST00000523905 and tumor protein 53-induced nuclear protein 1 (TP53INP1) were elevated in TMCs treated with H2O2. Similar to treatment with 3-MA (an inhibitor of autophagy), knocking-down the expression of TP53INP1 or ENST00000523905 could suppress the autophagy of TMCs induced by H2O2, which increased the level of ECM. Furthermore, the inhibition of ENST00000523905 decreased the expression of TP53INP1. ENST00000523905 could recruit and directly bind with CCAAT/enhancer (C/EBPβ), which can promote the expression of TP53INP1. Taken together, our findings demonstrated that ENST00000523905 may increase autophagy via enhancing TP53INP1 expression through binding with C/EBPβ, resulting in oxidative stress-induced decrease in ECM in HTMCs.
    Keywords:  Autophagy; Human trabecular meshwork cells; Long non-coding RNA; Oxidative stress; Tumor protein 53-induced nuclear protein 1
    DOI:  https://doi.org/10.1038/s41598-024-81300-6
  53. Eur J Med Chem. 2025 Jan 19. pii: S0223-5234(25)00058-3. [Epub ahead of print]287 117293
    Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations.
    Yanping Zeng, Jian Xiao, Li Shi, Yangsha Li, Yuanxin Xu, Jiayun Zhou, Xiao Dong, Haiyang Hou, Chao Zhong, Gang Cheng, Yi Chen, Naixia Zhang, Yanfen Fang, Youhong Hu.
      Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4-quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred via an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins.
    Keywords:  CDK9; Degradation; LC3B; Protein complex
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117293
  54. Int J Mol Sci. 2025 Jan 29. pii: 1170. [Epub ahead of print]26(3):
    Melatonin Mitigates Acidosis-Induced Neuronal Damage by Up-Regulating Autophagy via the Transcription Factor EB.
    Yan Shi, Zhaoyu Mi, Wei Zhao, Yue Hu, Hui Xiang, Yaoxue Gan, Shishan Yuan.
      Acidosis, a common feature of cerebral ischemia and hypoxia, results in neuronal damage and death. This study aimed to investigate the protective effects and mechanisms of action of melatonin against acidosis-induced neuronal damage. SH-SY5Y cells were exposed to an acidic environment to simulate acidosis, and a photothrombotic (PT) infarction model was used to establish an animal model of cerebral ischemia of male C57/BL6J mice. Both in vivo and in vitro studies demonstrated that acidosis increased cytoplasmic transcription factor EB (TFEB) levels, reduced nuclear TFEB levels, and suppressed autophagy, as evidenced by elevated p62 levels, a higher LC3-II/LC3-I ratio, decreased synapse-associated proteins (PSD-95 and synaptophysin), and increased neuronal apoptosis. In contrast, melatonin promoted the nuclear translocation of TFEB, enhanced autophagy, and reversed neuronal apoptosis. Moreover, the role of TFEB in melatonin's neuroprotective effects was validated by modulating TFEB nuclear translocation. In conclusion, melatonin mitigates acidosis-induced neuronal damage by promoting the nuclear translocation of TFEB, thereby enhancing autophagy. These findings offer new insights into potential treatments for acidosis.
    Keywords:  TFEB; acidosis; autophagy; melatonin; neuroprotective
    DOI:  https://doi.org/10.3390/ijms26031170
  55. J Virol. 2025 Feb 12. e0191224
    FBXO45 restricts HIV-1 replication by inducing SQSTM1/p62-mediated autophagic degradation of Tat.
    Mingxiu Xu, Haobo Hu, Weijing Yang, Jiaxiang Zhang, Hong Wang, Wenyan Zhang, Chen Huan.
      As a key regulator of human immunodeficiency virus type 1 (HIV-1) transcription, Tat plays an essential role in viral replication and latency, making it a promising target for designing viral control strategies. Identifying host factors that modulate Tat and exploring the underlying mechanisms will benefit our understanding of HIV-1 transcriptional regulation and provide valuable insights into Tat-based therapeutic strategies. Here, by employing the TurboID approach, we discovered high-affinity binding between FBXO45 and Tat. Our findings demonstrate that FBXO45 negatively regulates Tat by promoting Tat ubiquitination and directing it to autophagic degradation. Autophagic degradation of Tat has been reported, but the specific underlying mechanisms remain unidentified. We elucidated this issue by providing evidence that FBXO45-mediated Tat polyubiquitination is an essential prerequisite for this process. Silencing of FBXO45 leads to a deficiency of autophagy receptor SQSTM1/p62 to bind and facilitate the autophagic degradation of Tat. Our results further underscore the crosstalk between post-translational modifications of Tat by demonstrating that the phosphorylation site of the Tat S62 residue is required for ubiquitination induced by FBXO45. Furthermore, in the context of the regulation of HIV-1, FBXO45 inhibits viral replication and maintains the latency of HIV-1 by suppressing viral transcription. Importantly, FBXO45 overexpression significantly attenuated viral rebound after antiretroviral therapy withdrawal. In summary, our findings suggest a novel role for FBXO45 in regulating HIV-1 replication by inducing the ubiquitination and SQSTM1/p62-dependent autophagic degradation of Tat. Considering the indispensable role of Tat in the regulation of HIV-1 replication and reactivation, FBXO45 may be a potential target for therapeutic intervention against HIV-1.IMPORTANCEHIV-1 Tat plays an indispensable role in regulating viral transcription and is a promising target for achieving a functional cure for AIDS. Identifying the host factors that modulate Tat expression could benefit the development of anti-HIV-1 strategies targeting Tat. Using TurboID assay, we identified a significant interaction between FBXO45 and Tat. Functionally, FBXO45 ubiquitinates and directs Tat for SQSTM1/p62-mediated autophagic degradation, thereby effectively restricting HIV-1 replication and maintaining HIV-1 latency by suppressing Tat-dependent viral transcription. These findings uncover a novel role for FBXO45 in regulating Tat and broaden our understanding of the host mechanisms involved in Tat processing.
    Keywords:  FBXO45; HIV-1; Tat; autophagic degradation; transcription
    DOI:  https://doi.org/10.1128/jvi.01912-24
  56. Nat Aging. 2025 Feb 13.
    An mTOR paradox in sarcopenia via BCAA catabolism.
    Jerome N Feige.
      
    DOI:  https://doi.org/10.1038/s43587-025-00815-3
  57. Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00053-1. [Epub ahead of print]44(2): 115282
    Selective clearance of aberrant membrane proteins by TORC1-mediated micro-ER-phagy.
    Valeriya Gyurkovska, Yaneris M Alvarado Cartagena, Rakhilya Murtazina, Sarah F Zhao, Candela Ximenez de Olaso, Nava Segev.
      Aberrant accumulation and clearance of membrane proteins is associated with disease. Membrane proteins are inserted first to the endoplasmic reticulum (ER). During normal growth, two quality control (QC) processes, ER-associated degradation and macro-ER-phagy, deliver misfolded and excess membrane proteins for degradation in the proteasome and lysosome, respectively. We show that in yeast during normal growth, ER-QC is constitutive, since none of the stress-induced signaling pathways-nutritional, proteotoxic, or heat-are involved. In mutant cells defective in ER-QC, misfolded or excess proteins accumulate and nutritional stress, but not proteotoxic or heat stress, can stimulate their clearance. Early during nutritional stress, clearance occurs in the lysosome through a selective micro-ER-phagy pathway dependent on the ubiquitin ligase Rsp5, its Ssh4 adaptor, and ESCRT. In contrast, only a fraction of normal membrane proteins is degraded much later via macro-autophagy. Because the pathways explored here are conserved, nutritional stress emerges as a possible way for clearing disease-associated membrane proteins.
    Keywords:  CP: Cell biology; ER-quality control; ERAD; Endoplasmic reticulum; HSR; TORC1; UPR; macro-ER-phagy; micro-ER-phagy; nutritional stress
    DOI:  https://doi.org/10.1016/j.celrep.2025.115282
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