bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–06–07
57 papers selected by
Viktor Korolchuk, Newcastle University
  1. High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.
  2. Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.
  3. Autophagy decline during ageing: Molecular regulation, tissue specificity, and therapeutic potential.
  4. Deficient autophagy in retinal ganglion cells impairs the degradation of intracellular organelles, leading to neurodegeneration.
  5. From autophagy-lysosomal deficits to neurodegeneration in Niemann-Pick type C1 disease: implications for age-related neurodegenerative disorders.
  6. Evaluating the involvement of autolysosomes in the nuclear translocation of fluorescent proteins.
  7. Building the autophagosome: Molecular logic and membrane dynamics of autophagy.
  8. Harnessing Neuronal Autophagy: Bridging Mechanistic Breakthroughs to Therapeutic Interventions.
  9. TRIM21 induces selective autophagy of viruses and bacteria.
  10. Autophagic Pathway on GABARAP Involved in GABAA Receptor Trafficking.
  11. Autophagic pathway is responsible for selective degradation of cytosolic enzymes formaldehyde and formate dehydrogenases in the methylotrophic yeast Komagataella phaffii.
  12. Use it or lose it: A ubiquitin-mediated autophagy pathway for degradation of MHC-I in pancreatic cancer.
  13. [GLUT8- and AMPK-Dependent Autophagy Signaling in the Mechanism of the Neuroprotective Action of Trehalose].
  14. Mechanical Loading Induces the Radial Growth of Myofibrils and Myofibrillogenesis via an mTORC1-Dependent Mechanism.
  15. LASER couples damage sensing to ESCRT assembly for lysosome repair.
  16. p62 cleavage: a species-specific twist in TNF signalling.
  17. USP33 alleviates FIS1-dependent mitochondrial fission and cardiac microvascular injury in diabetic cardiomyopathy via deubiquitinating and stabilizing ATG7.
  18. WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway.
  19. AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
  20. Nucleophagy removes cytotoxic trapped PARP1.
  21. mTORC1-mediated inhibition of AMBRA1/PINK1/Parkin-dependent mitophagy contributes to renal podocyte injury in trichloroethylene-sensitized mice.
  22. Interplay between cohesin and TORC1 links chromosome segregation and gene expression to environmental changes.
  23. Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
  24. Simultaneous activation and late-stage inhibition of autophagy induces autophagy-dependent cell death in leukemia.
  25. Targeting HDAC6 and Its Novel E3 Ligase Activity: A Dual-Strategy for Cardiovascular Therapy.
  26. Berbamine sensitizes hepatocellular carcinoma to chemotherapy by inhibiting autophagy via modulating SIRT1-mediated acetylation.
  27. GPLD1 is a scavenger carrier mediating lysosomal degradation of extracellular aberrant proteins.
  28. Tbx20 and Sirt1 synergize to ameliorate cardiac aging through enhanced autophagy.
  29. SCM-1/SCAMP Maintains Microdomain Boundaries and Cargo Sorting within the Endosomal System.
  30. Vacuolar sorting receptors regulates autophagic trafficking of pathogenic effectors in plant immunity.
  31. A GUV-based assay to reconstitute membrane tethering in vitro.
  32. Autophagy supports the storage of lytic granules in human NK cells.
  33. Molecular mechanisms of autophagy-lysosomal pathway dysfunction in neurodegenerative diseases and therapeutic strategies for lysosomal repair: a review.
  34. The nuts-and-bolts of ribosomal protein s6 kinase 1 regulation: A shared responsibility for mTOR complexes 1 and 2.
  35. Loss of the mechanistic target of rapamycin complexes 1 (mTORC1) causes a lethal alpha-1 antitrypsin deficiency associated liver disease.
  36. A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
  37. Combined MEK1/2 and Autophagy Inhibition Suppresses Tumor Growth via STING-Mediated Type I Interferon Response in iCCA.
  38. CYLD-mediated lysine63 deubiquitination regulates synaptic transmission and autophagy to mitigate age-related sequelae.
  39. Lysosome-targeted near-infrared fluorescent probes for monitoring aβ plaques in vivo and aβ monomers dynamic degradation in vitro.
  40. Live cell imaging reveals paclitaxel-induced lysosome motility and function disruption in DRG neurons.
  41. Tumor stage-dependent expression of autophagy proteins in adrenocortical carcinoma.
  42. Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.
  43. Cardiac-derived extracellular vesicles carrying miR-4433b-3p accelerate cognitive decline and brain aging by suppressing TP53INP2-mediated neuronal autophagy in mice.
  44. Dietary pyrroloquinoline quinone and spermidine in healthy longevity: targeting the hallmarks of aging.
  45. FOXA1 protects against PM2.5-induced chronic lung injury via MARCHF8-dependent mitophagy inhibition.
  46. Mitophagy in Pulmonary Fibrosis: Molecular Interactions, Hypoxia Interactions, and Therapeutic Strategies.
  47. Diet-dependent sleep modulation by the Drosophila amino acid transporter ANIDRA.
  48. Role of homocysteine in renal tubular epithelial-mesenchymal transition: N-homocysteinylation of β-catenin impairs FUNDC1-dependent autophagy and mitochondrial quality control.
  49. ACE2 ameliorates DOX-induced cardiotoxicity by suppressing excessive autophagy via the AMPK/mTOR signaling pathway.
  50. Transcriptional and epigenetic regulation of autophagy: mechanisms, disease relevance and therapeutic opportunities.
  51. CLN7 suppression induces apoptosis via mTOR-regulated and chaperone-mediated autophagy in myeloid leukemia cells.
  52. Osteogenic promotion by naringin through the PI3K/AKT/mTOR pathway-mediated activation of autophagy and inhibition of apoptosis.
  53. Beyond Transport: Lysosomal solute carriers as orchestrators of immune signaling.
  54. CHK1 activates mitophagy to attenuate cardiac aging via inhibiting AHSA1-ubiquitination.
  55. AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer's disease.
  56. Atg8 orchestrates stress-responsive chromatin programs across immunity and metabolism.
  57. Mechanisms of NAD+ Homeostasis in Aging and Disease.
  1. Biochem Biophys Res Commun. 2026 Jun 01. pii: S0006-291X(26)00841-7. [Epub ahead of print]827 154077
    High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.
    Takashi Miyano, Kanzo Suzuki, Toshihiro Sera.
      Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway. It becomes active upon nuclear translocation and induces the expression of genes involved in autophagy and lysosomal function. Mechanistic target of rapamycin complex 1 (mTORC1) inhibition typically triggers this process; however, chronic mTORC1 suppression often induces adverse metabolic and proliferative effects, necessitating the identification of mTORC1-independent mechanisms driving TFEB nuclear translocation. Therefore, this study aimed to identify pharmacological activators of TFEB nuclear translocation that function independently of mTORC1 inhibition. In this study, we developed a high-content screening assay to quantify TFEB nuclear translocation in HeLa cells and screened a library of 560 approved compounds. We identified two compounds, NSC-319726 and ML-SA1, that promoted TFEB nuclear translocation without reducing p70S6K phosphorylation, supporting an mTORC1-independent mechanism. Both compounds significantly increased LC3-II accumulation and the signal intensity of an autolysosomal marker, indicating enhanced autophagic flux. Functionally, these compounds protected the cells against staurosporine-induced apoptosis and hydrogen peroxide-induced oxidative stress. Notably, pre-treatment conferred significantly greater protection than co-treatment, suggesting that TFEB-mediated transcriptional remodeling is necessary for maximal cytoprotection. Overall, these findings highlight the potential of high-content phenotypic screening to identify mTORC1-independent TFEB activators and suggest NSC-319726 and ML-SA1 as pharmacological inducers of protective autophagy in vitro.
    Keywords:  Autophagy; Cellular stress; Screening; TFEB; mTORC1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154077
  2. Autophagy. 2026 Jun 03.
    Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.
    Yuting Zhang, Jun Sun, Yixian Cui.
      Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) abnormalities are prominent features of Alzheimer's disease (AD), whether reticulophagy directly contributes to amyloid precursor protein (APP) turnover has remained unclear. We identify FAM134B/RETREG1 as a specific receptor that recognizes ER-localized APP and promotes its lysosomal degradation through LC3-dependent reticulophagy. In AD patient samples and 5XFAD mice, epigenetic repression of FAM134B limits TFEB/TFE3-dependent transcription, resulting in impaired ER turnover, APP accumulation, and exacerbated amyloid pathology. Restoration of wild-type, but not LIR-mutant, FAM134B rescues reticulophagy, reduces APP and Aβ accumulation, preserves neuronal integrity, and improves cognition in 5XFAD mice. These findings establish impaired reticulophagy as an upstream pathogenic mechanism in AD and highlight FAM134B-mediated ER turnover as a potential therapeutic strategy for limiting amyloidogenic APP accumulation.
    Keywords:  5XFAD mice; FAM134B/RETREG1; MAP1LC3B/LC3B; TFE3; TFEB; amyloid beta precursor protein; autophagy; epigenetic modification; lysosome; receptor
    DOI:  https://doi.org/10.1080/15548627.2026.2684514
  3. Pathol Res Pract. 2026 May 30. pii: S0344-0338(26)00221-9. [Epub ahead of print]286 156568
    Autophagy decline during ageing: Molecular regulation, tissue specificity, and therapeutic potential.
    Ahsas Goyal, Anshika Kumari, Neetu Agrawal, Harlokesh Narayan Yadav.
      During ageing, cell regulation has declined, as indicated by the buildup of damaged organelles and macromolecules and impaired proteostasis. Autophagy is a lysosome-based cell self-digestion mechanism that removes "cellular waste," which includes damaged organelles and abnormally altered proteins or protein aggregates. Thus, autophagy is a mechanism that is effective in maintaining normal cellular functioning via regulating the quality of proteins and organelles. However, ageing tissues and several age-related disorders have been demonstrated to have dysfunctional autophagy, resulting in the pathogenesis of cardiovascular, neurodegenerative, metabolic, muscular, and ocular disorders. Molecularly, dysregulation of nutrient-sensing pathways such as AMPK and mTOR, impaired transcriptional control by TFEB and FOXO, and reduced lysosomal competence contribute to the reduction of autophagy. Moreover, in several preclinical studies, pharmacological agents restore autophagic flux via inhibition of mTOR, activation of AMPK, and polyphenols, caloric restriction, and exercise (lifestyle interventions), show an effective role in the treatment of several disorders related to ageing. Furthermore, substantial pre-clinical data indicate the current knowledge about the molecular regulation of autophagy, its tissue-specific decline during ageing, and therapeutic strategies to restore autophagy to treat age-related disorders. Additionally, there is no clinical data available in order to confirm the safety and efficacy of their treatment, so a deeper study of autophagic modulation could serve as a basis for therapeutic interventions that encourage healthy ageing and delay age-related disorders in clinical models as well. Conclusively, according to several preclinical data, therapeutic measures show an effective role in treating several age-related disorders via targeting the autophagy pathway.
    Keywords:  Ageing; Autophagy; Molecular regulation; Pharmacological and lifestyle interventions; Proteostasis; Tissue specificity
    DOI:  https://doi.org/10.1016/j.prp.2026.156568
  4. Cell Death Dis. 2026 May 30.
    Deficient autophagy in retinal ganglion cells impairs the degradation of intracellular organelles, leading to neurodegeneration.
    Yogapriya Sundaresan, Prabhavathi Maddineni, Sarahi Rios Arguello, Balasankara Reddy Kaipa, Justin Dinh Tran, Linya Li, Bindu Kodati, Gulab S Zode.
      Autophagy is a fundamental catabolic process that facilitates the degradation and recycling of cellular components like protein aggregates and defective organelles. However, the precise role of constitutive autophagy in regulating retinal ganglion cell (RGC) function and survival remains largely undefined. Here, we demonstrate that RGCs exhibit a robust and highly active constitutive autophagy. Furthermore, the selective autophagy knockout in RGCs induces neurodegeneration in Atg7f/f and Atg5f/f conditional knockout mice. Deficient autophagy, induced by AAV2-Cre in Atg7f/f, Atg5f/f mice, or by tamoxifen treatment in Atg7f/-; Nestin-CreERT2+ mice, resulted in significant and progressive functional and structural loss of RGCs and optic nerve degeneration. Immunostaining and transmission electron microscopic analysis revealed that deficient autophagy in RGCs led to the accumulation of damaged organelles, including swollen mitochondria, distended endoplasmic reticulum, synaptic vesicles, and enlarged Golgi apparatus within the RGC soma. These pathological changes were associated with increased p62, LC3B, and incomplete autophagosomes in the RGC soma. Notably, mass spectrometry analysis identified the accumulation of proteins associated with intracellular organelles, cellular architecture, the cytoplasm, and the ribonucleoprotein complex. Our findings indicate that deficient autophagy in RGCs results in the accumulation of defective organelles within the RGC soma, ultimately contributing to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41419-026-08927-3
  5. Front Neurosci. 2026 ;20 1857866
    From autophagy-lysosomal deficits to neurodegeneration in Niemann-Pick type C1 disease: implications for age-related neurodegenerative disorders.
    Yuki Kawachi, Gamze Kocak, Viktor I Korolchuk, Tetsushi Kataura, Sovan Sarkar.
      Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by loss-of-function mutations in the NPC1 gene. NPC1 deficit primarily disrupts lipid homeostasis and subsequently drives cellular degeneration through mechanisms involving impaired autophagy and mitophagy, mitochondrial dysfunction, and, recently demonstrated NAD depletion that links autophagy impairment to neuronal death. Emerging evidence also highlights the activation of innate immune signaling leading to neuroinflammation. In this review, we synthesize current mechanistic insights and describe how these molecular deficits are interconnected to drive neuronal death in NPC1 disease. We also discuss how these pathological processes parallel those observed in major age-related neurodegenerative pathologies such as Alzheimer's and Parkinson's disease. Finally, we highlight emerging therapeutic strategies that can potentially ameliorate these cellular deficits, offering avenues for mitigating neurodegeneration in NPC1 disease and other related neurodegenerative disorders.
    Keywords:  NAD; NPC1; autophagy; cell death; lysosome; mitochondria; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3389/fnins.2026.1857866
  6. FEBS Open Bio. 2026 Jun 03.
    Evaluating the involvement of autolysosomes in the nuclear translocation of fluorescent proteins.
    Keiichi Ikeda.
      During the construction of control mCherry-labelled HeLa cells, we unexpectedly observed red fluorescence in cell nuclei and therefore investigated the mechanisms underlying the transport of fluorescent proteins (FPs) into the nuclei. We confirmed that mCherry and mCherry/EGFP tandem FPs were translocated into the nucleus and found that FPs are taken up by autophagosomes and translocated into the nucleus after entering lysosomes. However, pharmacological inhibition of autophagosome-lysosome fusion and syntaxin 17 knockdown decreased the nuclear translocation of mCherry in HeLa cells, but not in HepG2 cells, indicating that autophagy may also be involved in the nuclear translocation of FPs. Electron microscopy revealed that autolysosomes fused with the nuclear envelope and continued into the nucleus in HeLa cells but not in HepG2 cells, indicating that autophagy is involved in the nuclear translocation of FPs in HeLa cells. In addition, immunotransmission electron microscopy revealed that FPs can be transported directly into the nucleus through the nuclear pore complex. Our results suggest that autophagy is involved in the intracellular degradation and nuclear translocalisation of FPs.
    Keywords:  EGFP; autophagosome; lysosome; mCherry; nucleocytoplasmic transport; protein tracking
    DOI:  https://doi.org/10.1002/2211-5463.70279
  7. Curr Opin Cell Biol. 2026 May 30. pii: S0955-0674(26)00039-6. [Epub ahead of print]101 102651
    Building the autophagosome: Molecular logic and membrane dynamics of autophagy.
    Shilpa Gopan, Sharon A Tooze.
      Autophagy is initiated by the formation of a double-membrane autophagosome which is fine-tuned by the involvement of multiple protein machineries, organelles, and membrane pools. Autophagosome formation proceeds through steps requiring membrane nucleation, membrane expansion, and vesicle closure, initiated and coordinated by the cohort of ATG (Autophagy) proteins and lipids, such as PI(3)P and PE. Recent studies provide insights into how different molecular machineries act and interact to enable this complex vesicular pathway. Here, we review the current understanding of the steps that lead to autophagosome formation from a molecular perspective and, in this context, discuss the role of protein-membrane crosstalk in moulding the phagophore structure.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102651
  8. Aging Dis. 2026 May 19.
    Harnessing Neuronal Autophagy: Bridging Mechanistic Breakthroughs to Therapeutic Interventions.
    Nuzhat Ahsan, Farheen Badrealam Khan, Jhinuk Basu, Mohd Shariq, Nida Zaidi, Rizwan Hasan Khan, Reshmi Raj, Mohammed Akli Ayoub, Avadhesha Surolia, Ghulam Md Ashraf.
      Autophagy, an essential cellular process that degrades and recycles misfolded proteins, damaged organelles, and intracellular pathogens, is vital for neurons due to their limited capacity for apoptosis. Dysregulation of autophagy and lysosomal pathways is closely linked to the onset and progression of major neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In this manuscript, we offer a thorough examination of the molecular mechanisms that regulate autophagy, emphasizing both bulk and selective autophagy pathways and their roles in maintaining neuronal homeostasis. Genetic mutations in autophagy-related genes and endolysosomal genes are identified as significant risk factors, and the pathological roles of protein aggregation and mitochondrial dysfunction are also discussed. The therapeutic restoration of autophagic function represents a promising strategy for alleviating neurodegeneration. This manuscript examines potential interventions, including small molecules, gene therapy, and natural compounds, that enhance autophagic flux and facilitate protein clearance. Furthermore, the translational potential was underscored by including ongoing clinical trials that target autophagy pathways. This review artcile emphasizes the essential role of autophagy in neuronal health and disease, providing a framework for utilizing autophagic mechanisms to develop targeted therapeutic strategies for NDDs.
    DOI:  https://doi.org/10.14336/AD.2025.0804
  9. Mol Cell. 2026 Jun 04. pii: S1097-2765(26)00285-6. [Epub ahead of print]
    TRIM21 induces selective autophagy of viruses and bacteria.
    Tyler Rhinesmith, Anna Albecka, Marina Vaysburd, Claudia Puri, Jakub Luptak, Jerome Boulanger, Quynh-Mai Nguyen Le, Matthew J Gratian, Kevin O'Connell, Lara Few, Mark Donaldson-Wing, Patrycja Kozik, David C Rubinsztein, Leo C James.
      TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation. How the cell degrades these typically resistant substrates remains poorly understood. To address this, we used TRIM21 viral restriction to create a genome-wide phenotypic screen for antibody-dependent capsid degradation. We identify an antimicrobial selective macroautophagy pathway in mammalian cells, which we term "antibody-directed xenophagy" (ADX). We show that this mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella. Using quantitative microscopy, we demonstrate that TRIM21 rapidly intercepts antibody-pathogen complexes, leading to ubiquitin ligase activation. Following this, selective autophagy adaptors are recruited, and viral cargoes are delivered to lysosomes. This process reduces Salmonella pathology and bacterial tissue invasion in mice. We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.
    Keywords:  antibody; antimicrobial response; antiviral immunity; autophagy; innate immunity; protein degradation; targeted protein degradation; ubiquitin ligase; ubiquitin proteasome system; xenophagy
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.031
  10. Neurochem Res. 2026 Jun 01. pii: 182. [Epub ahead of print]51(3):
    Autophagic Pathway on GABARAP Involved in GABAA Receptor Trafficking.
    Mengqi Zhou, Wenjing Shi, Haoran Li, Jie Bai.
      The formation of lipidated Gamma-Aminobutyric Acid Receptor-Associated Protein (GABARAP), which is a crucial subfamily in the Autophagy-associated protein 8 (Atg8) group, not only requires the intricate collaboration of other autophagy-related proteins, but acts to necessarily promote the conduction of autophagy and Gamma-Aminobutyric Acid (GABA) A Receptor (GABAAR) trafficking. The molecular pathway on the formation of GABARAP is same as LC3-II, in which GABARAP is activated through Autophagy Activating Kinase 1 (ULK-1), Atg12-Atg5-Atg16L1 and Atg 4, whereas Rapamycin Complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) inhibit Ulk1. The lipidated GABARAP interacts with molecules related to the synapse and regulates GABAAR clustering through interactions with postsynaptic scaffolding proteins, such as gephyrin and Ankyrin. GABARAP plays roles in regulating synaptic functions besides autophagy.
    Keywords:  Autophagy; GABAAR; Synapse GABARAP
    DOI:  https://doi.org/10.1007/s11064-026-04803-w
  11. Sci Rep. 2026 Jun 01.
    Autophagic pathway is responsible for selective degradation of cytosolic enzymes formaldehyde and formate dehydrogenases in the methylotrophic yeast Komagataella phaffii.
    Olena V Dmytruk, Uliana I Pelypyshyn, Kostyantyn V Dmytruk, Andriy A Sibirny.
      In the methylotrophic yeast Komagataella phaffii (formerly Pichia pastoris), several methanol-induced enzymes are rapidly degraded upon a shift to glucose. We studied how deletion of autophagy-related genes affects turnover of two cytosolic enzymes, formaldehyde dehydrogenase (Fld1) and formate dehydrogenase (Fdh1), following the shift from methanol to glucose as a carbon source. GFP-tagged Fld1 and Fdh1 were expressed in wild-type and atg1Δ, atg6Δ, and atg15Δ strains, lacking, respectively, Atg1 (a serine/threonine kinase required for autophagosome formation), Atg6 (a subunit of phosphatidylinositol 3-kinase complexes I and II), and Atg15 (a phospholipase B required for lysis of autophagic bodies). Enzyme activities, Western blots, and fluorescence microscopy were used to monitor degradation. In wild-type cells Fld1 and Fdh1 levels and activities declined rapidly after the shift, whereas all atg1Δ, atg6Δ and atg15Δ mutants retained substantially higher Fld1/Fdh1 activity, similar to the peroxisomal enzyme alcohol oxidase, and cytosolic GFP signal. These data show that Atg1, Atg6 and Atg15 are required for efficient vacuolar degradation of cytosolic enzymes of methanol metabolism Fld1 and Fdh1. We conclude that these cytosolic enzymes are cleared via selective autophagy upon cell shift from methanol to glucose, underscoring the essential role of the autophagy-lysosome pathway in proteome remodeling of K. phaffii.
    Keywords:  ATG proteins; Carbon source shift; Protein turnover; Selective autophagy; Vacuolar proteolysis
    DOI:  https://doi.org/10.1038/s41598-026-54529-6
  12. Mol Cell. 2026 Jun 04. pii: S1097-2765(26)00313-8. [Epub ahead of print]86(11): 2035-2037
    Use it or lose it: A ubiquitin-mediated autophagy pathway for degradation of MHC-I in pancreatic cancer.
    Simon Wilkinson.
      In this issue of Molecular Cell, Berquez et al.1 reveal that MHC-I is degraded from within the endoplasmic reticulum (ER) by a ubiquitin-driven autophagy pathway involving co-operation of a cytoplasmic and an ER-phagy cargo receptor.
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.007
  13. Mol Biol (Mosk). 2026 Mar-Apr;60(2):60(2): 292-310
    [GLUT8- and AMPK-Dependent Autophagy Signaling in the Mechanism of the Neuroprotective Action of Trehalose].
    A B Pupyshev, M A Tikhonova.
      Trehalose disaccharide has a stable neuroprotective effect used in inhibiting experimental neurodegeneration. However, the mechanism of its action on brain neurons remains largely unclear. In hepatocytes, the main target of trehalose is the activation of mTOR-independent autophagy, which is achieved by inhibiting the glucose transporter GLUT8, leading to energy deficiency. An increase in AMP levels activates AMP-dependent kinase AMPK by phosphorylation at Thr172 and further activates autophagy regulator kinase ULK1. In neurons, the GLUT8 transporter inhibitors and other disaccharides also activate autophagy, but less effectively than trehalose. The neuroprotective effect of trehalose includes a chaperone-like effect, inhibition of the accumulation of aberrant proteins, reduction of oxidative stress, increased antioxidant protection, and suppression of neuroinflammation. Similar to the effect on hepatocytes, trehalose triggers the activation of autophagy by the short signaling pathway pAMPK-pULK1. AMPK inhibition prevents the activation of autophagy in neurons and weakens the neurotherapeutic effect of trehalose. AMPK activation is accompanied by the pleiotropic effect of suppression of biosynthetic processes and cellular metabolism related to activation of mTOR-dependent autophagy; however, no such effect has been detected for trehalose. In vivo data on the relationship among GLUT8 expression, AMPK activity, and autophagy levels in the brain are analyzed. The therapeutic advantages of the molecular effects of trehalose in comparison with the activation of mTOR-dependent autophagy and the possibilities of their combined therapeutic use are discussed.
    Keywords:  AMPK; GLUT8; TFEB; ULK1; hepatocytes; mTOR-independent autophagy; neurodegeneration; neurons; neuroprotection; trehalose
    DOI:  https://doi.org/10.7868/S3034555326020071
  14. bioRxiv. 2026 May 20. pii: 2026.05.18.725456. [Epub ahead of print]
    Mechanical Loading Induces the Radial Growth of Myofibrils and Myofibrillogenesis via an mTORC1-Dependent Mechanism.
    Corey Gk Flynn, Ramy K A Sayed, Anthony N Lange, Wenyuan G Zhu, Troy A Hornberger.
      Increased mechanical loading induces skeletal muscle growth and, at the ultrastructural level, promotes myofibrillogenesis and the radial growth of myofibrils. However, the mechanisms regulating these ultrastructural adaptations are not known. Here, we sought to determine whether the mechanistic target of rapamycin complex 1 (mTORC1) regulates these processes. To accomplish this, muscle-specific, tamoxifen-inducible raptor knockout (iRAmKO) mice were used to inhibit signaling through mTORC1, and growth was induced with a model of chronic mechanical overload (MOV). Using a next-generation fluorescence imaging pipeline for ultrastructural analyses, we found that mTORC1 is a critical regulator of the myofibrillogenesis and radial growth of myofibrils that occur in response to MOV. Together with other recent advances in the field, we propose a model in which mTORC1 acts as a gatekeeper that permits the retention, rather than the synthesis, of proteins that drive the ultrastructural adaptations.
    DOI:  https://doi.org/10.64898/2026.05.18.725456
  15. Nature. 2026 Jun 03.
    LASER couples damage sensing to ESCRT assembly for lysosome repair.
    Claire S Goul, Aakriti Jain, Samira Yitiz, Zahra E Soltani, Serim Yang, Simon Rapp, Martina Spacci, Scot Federman, James Sacco, Huinan Li, Lauren D Enriquez, Nalan Liv, Laralynne Przybyla, Roberto Zoncu.
      Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
    DOI:  https://doi.org/10.1038/s41586-026-10604-6
  16. Autophagy. 2026 Jun 03.
    p62 cleavage: a species-specific twist in TNF signalling.
    Olga Troitskaya, Christoph Nössing, Kevin M Ryan.
      Macroautophagy (hereafter referred to as autophagy) plays a key role in maintaining cellular homeostasis and shaping response to stress and inflammation. We report that inflammatory cytokines trigger caspase-8-dependent cleavage of the autophagy adaptor protein p62/SQSTM1 at aspartic acid 329 generating a truncated form (tr-p62). Tr-p62 enhanced TNF-induced cell death by stabilizing the RIPK1-dependent complex-IIb and amplifying caspase-8 activation, while having no detectable effect on necroptosis. Blocking autophagy caused tr-p62 accumulation and increased TNF-induced cell death, while non-cleavable p62 reduced autophagic responses and TNF sensitivity. Interestingly, mice naturally lack the caspase-8 cleavage site in p62 and restoring a cleavable version of p62 sensitized mouse cells to TNF-induced cell death. In addition, mice with cleavable p62 showed heightened sensitivity to TNF-induced toxic shock and chemical colitis in vivo. These findings identify p62 cleavage as a key regulator linking autophagy to TNF-driven inflammatory cell death and highlight an important species-specific difference that may influence the interpretation of inflammatory disease models.
    Keywords:  Autophagy; TNF; caspase; cell death; p62
    DOI:  https://doi.org/10.1080/15548627.2026.2684606
  17. Cell Death Dis. 2026 May 30.
    USP33 alleviates FIS1-dependent mitochondrial fission and cardiac microvascular injury in diabetic cardiomyopathy via deubiquitinating and stabilizing ATG7.
    Yuqiong Chen, Xiangyu Sun, Xinyan Li, Bo Guan, Xiaopei Yan, Chao Huang, Nannan Zhang, Wenjun Mao, Yuan Tian, Chao Chen, Yao Lu, Su Li.
      Endothelial dysfunction plays a key role in the development of diabetic cardiomyopathy (DCM), but the underlying mechanisms of endothelial dysfunction remain to be elucidated. Recent studies have revealed that dysregulated mitochondrial dynamics contributes to the development of cardiac microvascular dysfunction. Fission-1 (FIS1), a key effector of mitochondrial fission, functions as an outer mitochondrial membrane adapter that recruits dynamin-related protein-1 (Drp1) from the cytosol to the outer mitochondrial membrane for activating mitochondrial fission. The present study screened a library targeting deubiquitinases, and identified the regulatory role of USP33 on FIS1-dependent mitochondrial fission. We found USP33 silencing elevated FIS1 protein expression and resulted in excessive mitochondrial fission in endothelial cells, which in turn impaired mitochondrial function and worsen endothelial and cardiovascular dysfunction in DCM. Mechanistically, USP33 interacted with FIS1 at the TPR2 domain and promoted FIS1 degradation via lysosomal degradation. Further studies revealed that USP33 stabilized autophagy-related 7 (ATG7) at protein level by blocking K63-linked ubiquitination of human ATG7 at K48 (mouse K44) site. This process led to lysosomal degradation of FIS1 via ATG7-mediated autophagy. In summary, our findings reveal that USP33 plays a critical role in endothelial dysfunction in DCM and demonstrate that ATG7-FIS1 pathway acts as one of the potential downstream mechanisms.
    DOI:  https://doi.org/10.1038/s41419-026-08930-8
  18. Autophagy. 2026 Jun 03. 1-31
    WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway.
    Danqiong Liu, Yanling Cheng, Chuxiang Huang, Kang Xie, Jianan Jie, Qingqing Zhang, Lin Lan, Peiyu Chen, Jing Xie, Hongli Wang, Lu Ren, Huiwen Li, Lanlan Geng, Sitang Gong, Yun Zhu, Yang Cheng.
      WNT2B is canonically characterized as a secreted WNT-family ligand, which is transported to the extracellular space via the endoplasmic reticulum (ER)-Golgi pathway and binds to cell surface FZDs (frizzled class receptors) to trigger downstream signaling cascades. Here, we identify a previously unrecognized non-secretory intracellular function of WNT2B in impairing endosomal trafficking to inhibit macroautophagy/autophagy, as well as a non-canonical LC3B-II-dependent autophagic secretion mechanism for WNT2B. Specifically, the non-secretory intracellular pool of WNT2B via its conserved middle domain (MD) binds to the spectrin repeat domain (SRD) of WASHC5, competitively displacing WASHC1 and thereby disrupting WASH complex assembly and inhibiting WASHC1-mediated actin polymerization on early endosomes. This disruption impairs endosomal cargo trafficking, including the core autophagy protein ATG9A, leading to defective autophagy initiation and subsequent accumulation of pro-inflammatory and pro-fibrotic factors in fibroblasts. We validated this mechanism in vivo using a TNBS-induced mouse model of chronic colitis. Fibroblast-specific wnt2b deletion restores autophagy, reduces pro-inflammatory cytokine secretion, and ameliorates intestinal fibrosis. Consistently, in Crohn disease (CD) patient tissues, elevated WNT2B in fibrotic regions negatively correlates with autophagy activity, and positively correlates with pro-fibrotic phenotypes, and clinical disease severity. Moreover, we identify a novel LC3B-II-dependent autophagic secretion pathway for WNT2B, which is distinct from the conventional ER-to-Golgi-dependent protein secretion. Collectively, our study delineates a novel non-canonical WNT2B-WASH complex-ATG9A regulatory axis through which WNT2B impairs endosomal trafficking and disrupts autophagy, ultimately amplifying inflammation and fibrosis. This study suggests that WNT2B may serve as a promising therapeutic target for CD and autophagy-associated fibrotic disorders.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTA2: actin alpha 2, smooth muscle; ARPC2: actin related protein 2/3 complex subunit 2; ATG: autophagy related; CCN3: cellular communication network factor 3; CD: Crohn disease; CK666: 2-fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide; COL1A1: collagen type I alpha 1 chain; Co-IP: co-immunoprecipitation; CTNNB1: catenin beta 1; DBcAMP: dibutyryl cyclic adenosine monophosphate; DPT: dermatopontin; EEA1: early endosome antigen 1; EGFR: epidermal growth factor receptor; ELISA: enzyme-linked immunosorbent assay; ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; EV: extracellular vesicle; FRAP: fluorescence recovery after photobleaching; FL: full length; FZD: frizzled class receptor; GST: glutathione S-transferase; HIF: human intestinal fibroblast; HMGB1: high mobility group box 1; IKBKB: inhibitor of nuclear factor kappa B kinase subunit beta; IL6: interleukin 6; LDELS: LC3-dependent EV loading and secretion; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: middle domain; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; MVB: multivesicular body; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; PDCD6IP: programmed cell death 6 interacting protein; PLA: proximity ligation assay; RELA/p65: RELA proto-oncogene, NF-kB subunit; SAFB: scaffold attachment factor B; SES-CD: Simple Endoscopic Score for Crohn disease; SIM: super-resolution structured illumination microscopy; SMAD3: SMAD family member 3; SQSTM1/p62: sequestosome 1; SRD: spectrin repeat domain; TEM: transmission electron microscopy; TFRC: transferrin receptor; TGFB1: transforming growth factor beta 1; TGOLN2: trans-golgi network protein 2; TNBS: 2,4,6-trinitrobenzenesulfonic acid; TNF: tumor necrosis factor; VCA: Verprolin homology, Central and Acidic; WASHC: WASH complex subunit; WLS: Wnt ligand secretion mediator; WCL: whole cell lysates; WNT: Wnt family member; WT, wild type.
    Keywords:  ATG9A trafficking; Crohn disease; WASH complex; WNT-family protein; autophagic secretion; fibrosis
    DOI:  https://doi.org/10.1080/15548627.2026.2674714
  19. Nat Commun. 2026 Jun 05.
    AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
    Yuqin Wang, Raksha K Rao, Trung Vu, Ayano Sekine, Zhengmei Mao, Nami McCarty.
      Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling becomes essential during stress adaptation. In an acute liver-injury model, Amcf1 knock-in mice were fully protected, exhibiting elevated OPA1, reduced caspase-3 and PARP activation, and preserved Beclin 1. This functional duality reflects AMC-F1's ability to modulate the mitochondrial integrated stress response (mtISR), enabling adaptive ATF4 signaling while preventing maladaptive responses when stress exceeds a threshold. Autophagy upregulation by AMC-F1 is critical for fine-tuning the ISR and preserving cellular resilience. Together, our findings position AMC-F1 as a stress-responsive gatekeeper and a novel coordinator of mitochondrial-autophagy crosstalk, defining a cellular state primed for stress adaptation.
    DOI:  https://doi.org/10.1038/s41467-026-73841-3
  20. Nat Cell Biol. 2026 Jun 02.
    Nucleophagy removes cytotoxic trapped PARP1.
    Gwendoline Hoslett, Sara Tribble, Pauline Lascaux, Stelios Koukouravas, Ignacio Torrecilla, Wei Song, Cynthia X Hou, Junyi Li, Martín González-Fernández, Giuliana De Gregoriis, Rebecca A Dagg, Darragh O'Brien, Andrea Pierangelini, Thibaud Martial, Alvin Wei Tian Ng, Nuno Raimundo, Ira Milosevic, Raimundo Freire, Yuliang Li, Sven Rottenberg, Dragomir B Krastev, Christopher J Lord, Madalena Tarsounas, Kristijan Ramadan.
      Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HR)-deficient (HRD) cancers by trapping PARP1 on chromatin, thereby causing irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whereas autophagy inhibition can hypersensitize cells to PARPi. Our study reveals that trapped PARP1 is cleared via nucleophagy, with the selective autophagy receptor TEX264 and its partner segregase p97 (also known as VCP) orchestrating this process. TEX264 interacts directly with trapped PARP1, linking it to the autophagosomal protein LC3 for degradation. Disrupting this pathway, either chemically or genetically, increases PARP1 trapping, resulting in protein aggregates, DNA damage and cell lethality, ultimately re-sensitizing PARPi-resistant cells. We conclude that nucleophagy serves a cytoprotective role by targeting PARPi-induced trapped PARP1 for degradation.
    DOI:  https://doi.org/10.1038/s41556-026-01961-5
  21. Toxicol Appl Pharmacol. 2026 Jun 01. pii: S0041-008X(26)00190-0. [Epub ahead of print]513 117894
    mTORC1-mediated inhibition of AMBRA1/PINK1/Parkin-dependent mitophagy contributes to renal podocyte injury in trichloroethylene-sensitized mice.
    Qirui Bai, Chen You, Zhuohui Qin, Qixing Zhu, Haibo Xie.
      Trichloroethylene (TCE) is extensively utilized within industrial settings. Certain individuals with occupational exposure may develop occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT), with renal injury being a predominant clinical manifestation among OMDT patients. Prior research has demonstrated that TCE-sensitized mice exhibit glomerular podocyte damage and activation of the mTOR signaling pathway, although the precise mechanisms remain unclear. In the present study, we employed Rapamycin, an mTORC1 inhibitor, to intervene in a TCE-sensitized mouse model. This was complemented by TCE-sensitized mice serum-induced mouse podocyte clone-5 (MPC5) cell model to elucidate the mechanism through which mTORC1 contributes to podocyte damage during TCE sensitization. The findings indicate that activation of mTORC1 results in the downregulation of autophagy/beclin-1 regulator-1 (AMBRA1) expression. Following intervention with Rapamycin, there was a significant restoration of AMBRA1 expression in mice, accompanied by increased mitophagy and decreased apoptosis levels. In vitro studies using cell culture models demonstrated that MPC5 cells exposed to serum from TCE-sensitized mice showed markedly reduced expression of PINK1 and Parkin proteins, along with suppressed mitophagy levels. Treatment with Rapamycin or si-AMBRA1 effectively enhanced cellular mitophagy and diminished apoptosis. This study elucidates that TCE sensitization activates the mTORC1 signaling pathway, leading to the downregulation of AMBRA1. The suppression of AMBRA1 impedes the PINK1/Parkin-dependent mitophagy pathway, hindering the timely clearance of damaged mitochondria in podocytes. Consequently, this results in the release of cytochrome C into the cytoplasm, which triggers podocyte apoptosis signaling, compromises the integrity of the glomerular filtration barrier, and ultimately leads to renal dysfunction.
    Keywords:  AMBRA1; Apoptosis; Mitophagy; OMDT; mTORC1
    DOI:  https://doi.org/10.1016/j.taap.2026.117894
  22. Elife. 2026 Jun 01. pii: RP108275. [Epub ahead of print]14
    Interplay between cohesin and TORC1 links chromosome segregation and gene expression to environmental changes.
    Dorian Besson, Sabine Vaur, Stéphanie Vazquez, Sylvie Tournier, Yannick Gachet, Adrien Birot, Stéphane Claverol, Adèle L Marston, Anastasios Damdimopoulos, Karl Ekwall, Jean-Paul Javerzat.
      Cohesin is a DNA tethering complex essential for chromosome structure and function. In fission yeast, defects in the cohesin loader Mis4 result in chromosome segregation defects and dysregulated expression of genes near chromosome ends. A genetic screen for suppressors of the thermosensitive growth defect of mis4-G1487D identified several hypomorphic mutants of the Target of Rapamycin Complex 1 (TORC1), a conserved kinase that integrates cellular signals to regulate growth and metabolism through substrate-specific phosphorylation. Here, we demonstrate that the TORC1 pathway modulates cohesin functions in chromosome segregation and gene expression. In the context of compromised cohesin loading, the incidence of chromosome segregation defects was modulated by the growth medium in a TORC1-dependent manner. Pharmacological or genetic downregulation of TORC1 activity restored cohesin binding to its chromosomal sites and improved mitotic chromosome segregation. Notably, reduced TORC1 activity also increased cohesin binding and chromosome transmission fidelity in wild-type cells. These results suggest that environmental cues influence chromosome stability via TORC1. Biochemically, TORC1 co-purified with cohesin and reduced TORC1 activity correlated with decreased phosphorylation of specific residues on Mis4 and cohesin. Mutations in cohesin that mimic the non-phosphorylated state mirrored the effects of TORC1 downregulation, showing that TORC1 is part of the network that controls cohesin phosphorylation to modulate its functions. Finally, we show that the functional interaction between TORC1 and Mis4 extends to the regulation of stress-responsive genes. Our findings reveal a TORC1-cohesin link that may facilitate cellular adaptation to environmental changes. Given that TORC1 inhibitors and calorie restriction extend lifespan in diverse species, this connection raises the intriguing possibility that cohesin-mediated changes in chromosome structure contribute to these effects.
    Keywords:  S. pombe; TORC1; adaptive response; chromosome segregation; chromosomes; cohesin; gene expression; phosphorylation
    DOI:  https://doi.org/10.7554/eLife.108275
  23. NPJ Aging. 2026 Jun 03.
    Targeting mitophagy for neuroprotection: mechanisms and therapeutic opportunities.
    Jiahui Yang, Jianfeng Li, Xintong Hou, Yifei Zheng, Zeyu Zhao, Ting Zhou, Tongwei Jing, Jiming Kong, Guohui Zhang, Ying Guo.
      Mitochondria are essential for neuronal energy production, cellular homeostasis, and overall neuronal function. Due to their high metabolic demands and limited regenerative capacity, neurons are particularly vulnerable to mitochondrial dysfunction, which leads to ATP depletion, excessive reactive oxygen species (ROS) production, and calcium imbalance-ultimately causing oxidative stress, metabolic disruption, and neuronal death. Mitophagy is a selective process that removes damaged mitochondria through the autophagy-lysosome pathway. As a key mechanism of mitochondrial quality control, mitophagy preserves energy production, limits oxidative damage, and maintains mitochondrial network integrity. This process is regulated by pathways such as PINK1-Parkin and receptor-mediated mechanisms involving BNIP3 and FUNDC1, all of which help sustain cellular health by preventing mitochondrial dysfunction. Impaired mitophagy is a common feature of several neurodegenerative diseases, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease, exacerbating mitochondrial damage and neuronal stress. Emerging therapeutic strategies that target mitophagy-ranging from pharmacological agents and gene therapies to dietary interventions-show promise in restoring mitochondrial quality and protecting neurons from degeneration. Nevertheless, challenges remain in translating these findings into effective clinical treatments. Mitophagy represents a critical mechanism for preserving neuronal integrity and offers a compelling target for innovative therapies against neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41514-026-00424-3
  24. BMC Cancer. 2026 Jun 04.
    Simultaneous activation and late-stage inhibition of autophagy induces autophagy-dependent cell death in leukemia.
    Yie Wei Chua, Sek Chuen Chow.
       BACKGROUND: Resistance to apoptosis is a major challenge in cancer therapy, especially in relapsed or refractory leukemia. Autophagy, a conserved lysosomal degradation pathway, plays a complex dual role: it can promote tumor survival under stress, yet its excessive activation can trigger autophagy-dependent cell death (ACD). This paradox has inspired a novel therapeutic strategy that simultaneously activates and inhibits specific stages of autophagy to push cells toward death. However, the molecular mechanisms underlying this approach remain poorly understood, particularly in non-solid tumors like leukemia.
    METHODS: This study investigated the effects of simultaneous autophagy activation and stage-specific inhibition on cell death in human Jurkat E6.1 leukemic T cells. Cells were treated with rapamycin (RAPA) to induce autophagy, combined with either chloroquine (CQ) to block late-stage degradation or 3-methyladenine (3-MA) to inhibit early-stage autophagosome formation. Cell viability was measured by MTS assay, while autophagy flux was evaluated using a combination of MDC staining, mCherry-eGFP-LC3 fluorescence imaging and Western blot analysis for LC3. To delineate the mode of cell death, we accessed apoptosis via caspase-3 cleavage and employed pharmacological inhibitors of apoptosis (z-VAD-FMK) and necrosis (Necrostatin-1).
    RESULTS: Simultaneous autophagy induction with RAPA and late-stage inhibition with CQ (RAPA + CQ) triggered massive autophagosome accumulation and significantly enhanced cell death. In contrast, early-stage inhibition with 3-MA (RAPA + 3-MA) prevented autophagic vesicle formation and abrogated the cytotoxic effect. Importantly, this cell death occurred independently of both apoptosis and necroptosis, suggesting a direct result of excessive and unprocessed autophagosomes, consistent with ACD.
    CONCLUSION: In conclusion, our findings demonstrate that trapping cells in a state of high autophagic flux through simultaneous induction and late stage inhibition, is a potent strategy to trigger non-apoptotic cell death in leukemia. This approach represents a promising therapeutic strategy to overcome apoptosis-resistant leukemia.
    Keywords:  Autophagy; Autophagy-dependent cell death; Chloroquine; Leukemia; Rapamycin
    DOI:  https://doi.org/10.1186/s12885-026-16102-2
  25. Ageing Res Rev. 2026 Jun 02. pii: S1568-1637(26)00192-3. [Epub ahead of print] 103200
    Targeting HDAC6 and Its Novel E3 Ligase Activity: A Dual-Strategy for Cardiovascular Therapy.
    Xingjuan Shi, Ziyang Zhao, Weiying Yue, Shiyi Feng, Nan Zhang, Xiaoou Sun.
      Cardiovascular disease, the leading cause of death worldwide, imposing an enormous economic burden on society. Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, contains two tandem deacetylase domains. Recent study reported that the first deacetylase domain of HDAC6 exerts E3 ligase activity. It is known that HDAC6 participates in a variety of cellular activities including microtubule stability, epithelial homeostasis and autophagy by modulating its specific non-histone substrates. However, the role of HDAC6 and its selective inhibitors in cardiovascular disease remains unclear. In this paper, we focus on the role of HDAC6 in the heart, as well as in the progression of cardiovascular disease including heart failure, cardiomyopathy, cardiotoxicity and myocardial infarction. We find that the expression of HDAC6 is elevated in various cardiovascular diseases, suggesting that HDAC6 may act as a biomarker for cardiovascular disease. We further discuss the potential of depletion of Hdac6 or the application of its selective inhibitors in disease prevention and treatment. Elucidation of these issues indicate that HDAC6 and its selective inhibitors might act as potential therapeutic targets for cardiovascular disease.
    Keywords:  Cardiovascular disease; E3 ligase; HDAC6; HDAC6 selective inhibitor
    DOI:  https://doi.org/10.1016/j.arr.2026.103200
  26. Front Pharmacol. 2026 ;17 1763828
    Berbamine sensitizes hepatocellular carcinoma to chemotherapy by inhibiting autophagy via modulating SIRT1-mediated acetylation.
    Qin Peng, Ling Xiao, Xinhui Huang, Ziyuan Huang, Guangxian Zhang, Jihong Zhou, Yuhui Tan.
      Chemoresistance driven by pro-survival autophagy remains a major obstacle in hepatocellular carcinoma (HCC) treatment. Berbamine (BBM), a natural alkaloid with a favorable clinical safety profile, shows potential as an autophagy inhibitor, yet its precise mechanism in HCC remains unclear. Using CCK-8, colony formation, and apoptosis assays, we first demonstrated that BBM synergistically enhanced the efficacy of multiple chemotherapeutic agents (5-FU, Sorafenib, Paclitaxel) against HCC cells in vitro. This synergistic effect was confirmed in an H22 xenograft mouse model in vivo. To investigate the mechanism, we monitored autophagic flux and lysosomal function. Western blot and immunofluorescence analyses revealed that BBM treatment led to the concurrent accumulation of LC3-II and p62, indicating a blockade of late-stage autophagic flux. Further experiments, including LysoTracker staining and assessment of lysosomal protease levels, showed that BBM impaired both autophagosome-lysosome fusion and lysosomal acidification. Mechanistically, we found that BBM downregulated SIRT1 protein expression and reduced the intracellular NAD+/NADH ratio, thereby inhibiting SIRT1 deacetylase activity. This suppression impaired the nuclear translocation and function of the key autophagy transcription factor TFEB, leading to decreased levels of its downstream targets RAB7, CTSB, and CTSD. Crucially, rescue experiments using specific agonists revealed that SIRT1 activation completely reversed all BBM-induced effects, including autophagic flux blockade and downstream protein suppression, whereas TFEB activation only partially rescued the expression of RAB7, CTSB, and CTSD without restoring autophagic flux. This establishes SIRT1 as the primary upstream regulator in this pathway. Our study identifies BBM as a novel autophagy inhibitor that targets the SIRT1-TFEB axis to disrupt autolysosomal fusion and degradation, and nominates it as a promising combinational agent to overcome chemoresistance in HCC.
    Keywords:  SIRT1; TFEB; autophagy; berbamine; chemosensitivity; hepatocellular carcinoma
    DOI:  https://doi.org/10.3389/fphar.2026.1763828
  27. Life Sci Alliance. 2026 Aug;pii: e202603717. [Epub ahead of print]9(8):
    GPLD1 is a scavenger carrier mediating lysosomal degradation of extracellular aberrant proteins.
    Mizuki Tsuchiya, Yoichiro Yagishita, Eisuke Itakura.
      Loss of proteostasis leads to the accumulation of aberrant proteins, including aggregated proteins and amyloid fibrils, contributing to various diseases. Protein quality control systems are essential for maintaining proteostasis. Although intracellular mechanisms are well characterized, pathways responsible for the degradation of aberrant proteins outside the cell remain poorly understood. We previously identified the chaperone/carrier- and receptor-mediated extracellular protein degradation pathway, in which the extracellular chaperone clusterin binds misfolded proteins and the resulting complex is delivered to lysosomes via endocytosis. However, it remains unclear whether other factors are involved in this pathway. To identify novel regulators, plasma factors binding serum amyloid A1 were investigated. Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) was found to directly bind serum amyloid A1 and promote its lysosomal degradation. This activity was independent of GPLD1's cleavage activity for GPI-anchored proteins. Furthermore, GPLD1 mediates lysosomal degradation of misfolded proteins, with cell surface heparan sulfate acting as its receptor. Our data demonstrate that GPLD1 is a novel scavenger carrier with substrate specificity distinct from clusterin, responsible for degrading extracellular aberrant proteins.
    DOI:  https://doi.org/10.26508/lsa.202603717
  28. Tissue Cell. 2026 Jun 01. pii: S0040-8166(26)00347-2. [Epub ahead of print]103 103654
    Tbx20 and Sirt1 synergize to ameliorate cardiac aging through enhanced autophagy.
    Riffat Khanam, Pabitra Mandal, Madhurima Khamaru, Parna Dutta, Madhurima Ghosh, Devrani Mitra, Arunima Sengupta, Santanu Chakraborty.
      Cardiovascular diseases are a cause of global concern with age being a major contributor to failing hearts. Even in aged individuals with no cardiac anomalies, cardiac physiology and functioning are severely affected and so is autophagy. Unfortunately, with aging, there is a decline in the functionality of autophagic machinery, and impaired autophagy sustains which worsens cardiac functioning. Here, in this study we have highlighted for the first time, the autophagy induced role of Tbx20 as a regulatory factor mediating the expression of cardiomyocyte progenitor markers like Nkx2.5 and Gata4 along with stimulating the expression of anti-senescence markers GSK-3β and especially Sirtuin1 (Sirt1), a known anti-senescent and an anti-aging marker to express in heart. Our study relied on two model systems: H9c2, rat cardiomyoblast cell line as the in-vitro model and the aged murine model system as part of the in-vivo system. Starvation and Rapamycin administration/ treatment were performed to induce autophagy in both the model systems. Immunostaining and Western Blotting (WB) were performed to assess the expression of Tbx20, Nkx2.5, Gata4 and GSK-3β. In-silico affinity binding assay showed a favourable interactions between Tbx20 and Sirt1 DNA later validated by ChIP assay. Finally, Tbx20 siRNA mediated knockdown was performed in H9c2 cell line to assess its regulatory role. The Tbx20-dependent expression pattern of Nkx2.5, Gata4, GSK-3β and Sirt1 highlights the master regulatory role of Tbx20 following autophagy induction. Most importantly, the novel interaction between Tbx20 and Sirt1 opens possibilities for how Tbx20 might regulate senescence and the fact that diminishing levels of Tbx20 in aging adults corroborates with declining levels of Sirt1.
    Keywords:  Cardiovascular disease; Sirt; Tbx20; autophagy; cardiac aging; cardiac progenitor
    DOI:  https://doi.org/10.1016/j.tice.2026.103654
  29. bioRxiv. 2026 May 20. pii: 2026.05.20.726532. [Epub ahead of print]
    SCM-1/SCAMP Maintains Microdomain Boundaries and Cargo Sorting within the Endosomal System.
    Kam Shan Hu, Anne Norris, Wilmer Rodriguez-Polanco, Collin McManus, Inna A Nikoronova, Geoffrey G Hesketh, Anne-Claude Gingras, Maureen M Barr, Barth D Grant.
      After endocytosis, transmembrane cargo reaches sorting endosomes where it is partitioned into physically distinct recycling or degradative microdomains. While the J-domain protein RME-8/DNAJC13 is known to maintain these boundaries by actively removing degradative machinery from the recycling microdomain, other factors that contribute to this spatial organization remain poorly defined. Here, we identify the conserved tetraspan protein SCM-1/SCAMP as a key microdomain organizer, discovered through RME-8 proximity-dependent biotinylation screens in C. elegans and human cells. Leveraging the large endosomes of C. elegans coelomocytes, we show that SCM-1 is selectively enriched within the recycling microdomain. In scm-1 mutants, recycling and degradative microdomains still assemble but fail to remain spatially distinct, resulting in inappropriate microdomain overlap. This loss of boundary integrity occurs without increasing the recruitment of sorting machineries, indicating a mechanism distinct from the RME-8-mediated uncoating pathway. scm-1 mutants exhibit significant sorting defects, including misrouting of recycling cargo MIG-14/Wls and v-SNARE SNB-2/VAMP3 to late endosomes and lysosomes. We find that snb-2 mutants themselves missort MIG-14 to late endosomes and lysosomes, suggesting that SNB-2 sorting is key for recycling function. Our data suggest that both microdomains lose efficiency in scm-1 mutants, as cargo missorted into late endosomes and lysosomes is not depleted overall, and degradation of an independent ESCRT-dependent cargo is delayed. We conclude that SCM-1 ensures endosomal sorting fidelity by stabilizing microdomain boundary integrity, a process required for efficient recycling and degradation of transmembrane cargo.
    DOI:  https://doi.org/10.64898/2026.05.20.726532
  30. Autophagy. 2026 Jun 03.
    Vacuolar sorting receptors regulates autophagic trafficking of pathogenic effectors in plant immunity.
    Shuai Hu, Dongmei Zhu, Yanli Gao, Enrique Rojo, Jinbo Shen.
      Selective autophagy functions not only in nutrient recycling and stress adaptation but also in the degradation of pathogen-derived virulence effectors during effector‑triggered immunity (ETI). However, how vacuolar sorting receptors (VSRs) coordinate endomembrane trafficking and selective autophagy during ETI remained poorly understood. In a recent study, we identified four pathogen‑inducible VSRs (VSR1, VSR5, VSR6, VSR7) that play important roles in regulating vacuolar cargo sorting, tonoplast - plasma membrane fusion, and hypersensitive cell death during ETI. Importantly, upon pathogen invasion and immune activation, VSR1 dynamically relocalized from the prevacuolar compartment/multivesicular body (PVC/MVB) to ATG8-positive autophagosomes. Moreover, loss of VSR function impaired autophagic flux and disrupted degradation of bacterial effectors. These observations illustrated a model in which pathogen-responsive VSRs function as a trafficking hub, integrating secretory and effector-phagy to enable rapid and effective plant immunity during ETI.Abbreviations:VSRs, vacuolar sorting receptors; TGN, trans-Golgi network; PVC/MVB, prevacuolar compartment/multivesicular body; ETI, effector‑triggered immunity; P. syringae,Pseudomonas syringae; PM, plasma membrane; NLR, nucleotide-binding leucine-rich repeat; HR, hypersensitive response; ECS, extracellular space; NPR1, nonexpressor of pathogenesis-related genes 1; AP, adaptor protein; PLCPs, pathogen-inducible papain-like cysteine proteases; ATG, autophagy-related; NBR1, neighbor of BRCA1 gene 1 protein; FLS2, FLAGELLIN-SENSING 2.
    Keywords:  Autophagy; ETI; effector-phagy; pathogenic effectors; vacuolar sorting receptors
    DOI:  https://doi.org/10.1080/15548627.2026.2684463
  31. Mol Biol Cell. 2026 Jun 03. mbcE25110531
    A GUV-based assay to reconstitute membrane tethering in vitro.
    Devika Andhare, Michael J Ragusa.
      Membrane tethering is essential for the generation of organelle contact sites, the catabolic process of autophagy and to anchor incoming vesicles to their target membranes before vesicle fusion. While membrane tethering is critical for cellular function, many of the current biochemical techniques to test for membrane tethering rely on indirect readouts and are limited in their ability to monitor protein localization at sites of tethering. As such, we recently developed a fluorescence microscopy-based giant unilamellar vesicle and liposome tethering assay (GLT) to study the membrane tethering properties of two autophagy proteins. In this study, we used GLT with engineered membrane tethers to demonstrate the ease of use, methods of analysis, versatility and sensitivity of the assay. We demonstrate that: 1) GLT can be used to study liposome tethering, fusion and phosphatase mediated detethering of tethered liposomes, 2) GLT detects tethering with comparable sensitivity to less direct methods for monitoring membrane tethering while allowing simultaneous monitoring of membrane and protein localization, and 3) GLT can be used to monitor the kinetics of membrane tethering in real time. Collectively, our results demonstrate GLT is a broadly useful method to study membrane tethering in vitro. [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-11-0531
  32. Cell Death Dis. 2026 Jun 01.
    Autophagy supports the storage of lytic granules in human NK cells.
    Piera Filomena Fiore, Sergio Forcelloni, Simone Vitozzi, Nicola Tumino, Tobias Theinert, Lokossou William Sanvi, Francesca Nazio, Valentina D'Oria, Stefania Martini, Maximilian Reichert, Lorenzo Moretta, Ignazio Caruana, Paola Vacca.
      Natural Killer (NK) cells are innate lymphoid cells that play an important role in immune defense against pathogens and tumors. Understanding the mechanisms that enhance NK cell effector functions could significantly improve current NK cell-based therapies. Autophagy is a lysosome-dependent degradation process essential for NK cell development and function. This study analyzed the autophagic potential of mature NK cell subsets in peripheral blood. We demonstrated that exposure to inflammatory cytokines reduces autophagy via mTOR signaling pathway. Specifically, the activation of NK cell receptors leads to a temporary decrease in autophagy, which is rapidly restored, demonstrating the dynamics of autophagy in response to activating signals. Importantly, continuous overexpression of key autophagy regulators significantly increased autophagic flux, which directly correlated with enhanced cytotoxicity and metabolic activity in NK cells. The increased cytotoxicity was supported by a greater accumulation of cytolytic granules and their associated proteins. Our findings indicate that activating stimuli reduce autophagy, whereas sustained autophagic activity under steady-state conditions is crucial for the formation and maintenance of cytolytic granules, supporting the persistent cytotoxic function of NK cells.
    DOI:  https://doi.org/10.1038/s41419-026-08937-1
  33. Front Neurosci. 2026 ;20 1819002
    Molecular mechanisms of autophagy-lysosomal pathway dysfunction in neurodegenerative diseases and therapeutic strategies for lysosomal repair: a review.
    Weilin Wang, Xianguo Meng.
      The autophagy-lysosomal pathway (ALP) is a critical intracellular protein degradation system responsible for maintaining proteostasis and metabolic balance within cells. Dysfunction of this pathway has been increasingly recognized as a key pathological basis underlying various neurodegenerative diseases (NDs). This review provides a comprehensive overview of the molecular mechanisms by which ALP impairment contributes to defective protein degradation in neurodegeneration. We focus on the impact of lysosomal structural integrity and functional imbalance on cellular fate, highlighting the interplay between protein oxidative damage and degradation system dysregulation. Furthermore, we summarize the current therapeutic strategies aimed at lysosomal repair, evaluating their potential clinical applications and efficacy. By integrating the latest research advances, this review aims to deepen the understanding of the pathological mechanisms of autophagy-lysosomal pathway dysfunction in neurodegenerative diseases, clarify the key molecular targets of lysosomal damage and repair, and provide theoretical basis for target screening and validation and practical reference for the development of targeted drugs for neurodegenerative diseases.
    Keywords:  autophagy-lysosomal pathway; lysosomal repair; molecular mechanisms; neurodegenerative diseases; protein degradation; therapeutic strategies
    DOI:  https://doi.org/10.3389/fnins.2026.1819002
  34. FEBS J. 2026 Jun 05.
    The nuts-and-bolts of ribosomal protein s6 kinase 1 regulation: A shared responsibility for mTOR complexes 1 and 2.
    Sheikh Tahir Majeed, Rabiya Majeed, Khurshid I Andrabi.
      Ribosomal protein S6 kinase 1 (S6K1) is a master regulator of cell growth and metabolism and a primary effector of the mTOR signaling pathway. Given its central role in cancer and metabolic diseases, S6K1 is a high-priority therapeutic target; however, developing effective treatments requires a definitive understanding of how the enzyme is activated. This review provides a comprehensive synthesis of S6K1 biology, covering its structural domains, various chemical modifications like acetylation and ubiquitination, and its regulation by noncoding RNAs. We specifically highlight the transition from traditional 'canonical' models to an emerging 'non-canonical' paradigm. Central to this shift is the proposal that S6K1 activation is a shared responsibility between two complexes: mTORC1 and mTORC2. We detail a two-step mechanism where mTORC1 first 'primes' the enzyme by relieving internal constraints, allowing mTORC2 to complete the activation process. By reconciling these different models and addressing long-standing questions about drug sensitivity, this review establishes a modern framework for S6K1 biology and identifies new opportunities for precise therapeutic intervention.
    Keywords:  eIF4E; mTORC1; mTORC2; phosphorylation; rapamycin; ribosomal protein S6 Kinase 1; signal transduction
    DOI:  https://doi.org/10.1111/febs.70612
  35. Cell Mol Gastroenterol Hepatol. 2026 Jun 04. pii: S2352-345X(26)00102-5. [Epub ahead of print] 101824
    Loss of the mechanistic target of rapamycin complexes 1 (mTORC1) causes a lethal alpha-1 antitrypsin deficiency associated liver disease.
    Lisa Bewersdorf, Sophie Haber, Ines Volkert, Katharina Remih, Annika Gross, Christian Preisinger, Linda Kroll, Thorsten Cramer, Nadine Therese Gaisa, Sophie Leypold, Ulrike Rolle-Kampczyk, Nicola Brunetti-Pierri, Martin von Bergen, Florian Rosenberger, Caroline Weiss, Nurdan Guldiken, Pavel Strnad.
       BACKGROUND & AIMS: SERPINA1 mutations cause retention of the otherwise secreted alpha-1 antitrypsin (AAT) and lead to the proteotoxic AAT deficiency (AATD)-related liver disease (AATD-LD). As mechanistic target of rapamycin (mTOR) is a key coordinator of proteostasis, we studied its role in AATD-LD.
    METHODS: PiZ mice overexpressing the characteristic SERPINA1 mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mTOR (RAPTOR) or rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) corresponding to mTOR complexes 1 or 2 (mTORC1/2) or with mice lacking mTOR. Serum proteomics, liver bulk proteomics, spatial proteomics, and metabolomics were applied to characterize molecular and metabolic alterations.
    RESULTS: At two months of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of increased liver injury and mortality despite diminished hepatic AAT accumulation. PiZ-RaptorΔhep animals displayed increased levels of the pro-apoptotic protein C/EBP homologous protein (CHOP), but CHOP ablation did not rescue the phenotype. Serum proteomics revealed no signs of advanced synthetic liver failure but immature hepatocellular products. Liver bulk proteomics and small metabolite measurement demonstrated a metabolic reprogramming of PiZ-RaptorΔhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-RaptorΔhep animals.
    CONCLUSIONS: In summary, in AATD-related proteotoxic liver injury, Raptor preserves a liver zonation, thereby protecting from lethal metabolic dysregulation.
    Keywords:  hyperammonemia; liver zonation; metabolic reprogramming; proteostasis
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101824
  36. J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):
    A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
    Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.
      Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.
    DOI:  https://doi.org/10.1083/jcb.202511088
  37. Cancer Sci. 2026 Jun 02.
    Combined MEK1/2 and Autophagy Inhibition Suppresses Tumor Growth via STING-Mediated Type I Interferon Response in iCCA.
    Chengqiang Sun, Zheng Gao, Enfu Dong, Liangxia Ding, Shanru Feng, Jiafeng Chen, Pascal Kwangwari, Yinghong Shi, Weiren Liu, Xin Zhang, Ao Huang, Jian Zhou, Sheng Wang, Jia Fan, Xiutao Fu, ZhenBin Ding.
      The RAF-MEK-ERK pathway contributes to many human cancers, including intrahepatic cholangiocarcinoma (iCCA). Although MEK is an important therapeutic target, MEK inhibitors (MEKis) have limited efficacy as monotherapy in iCCA, and the underlying adaptive mechanisms remain unclear. Here, we show that MEK inhibition induces protective autophagy in iCCA cells. Mechanistically, MEK inhibition suppressed ERK-RSK signaling, activated the LKB1-ULK1 pathway, and promoted autophagy. MEK inhibition also increased reactive oxygen species (ROS) accumulation and activated PINK1/Parkin-mediated mitophagy. This autophagic response limited activation of the cGAS-STING-TBK1 pathway. Pharmacological or genetic inhibition of autophagy during MEK inhibition enhanced STING-mediated type I interferon signaling, increased IFN-α and IFN-β expression, and sensitized iCCA cells to MEKi treatment. Consistently, combined MEK and autophagy inhibition suppressed tumor growth in xenograft-bearing nude mice. These findings identify a link between MAPK signaling, autophagy, and innate immune sensing and support targeting the MEK-autophagy-STING axis to improve MEKi efficacy in iCCA.
    Keywords:  MEK; autophagy; cGAS‐STING signaling pathway; interferon type I; intrahepatic cholangiocarcinoma
    DOI:  https://doi.org/10.1111/cas.70436
  38. Nat Commun. 2026 Jun 04.
    CYLD-mediated lysine63 deubiquitination regulates synaptic transmission and autophagy to mitigate age-related sequelae.
    Aggeliki Sotiriou, Georgios Konstantinidis, Nektarios Tavernarakis.
      Lysine63 polyubiquitination is a prevalent post-translational modification in the central nervous system. Deficiency of CYLD, a lysine63-specific deubiquitinase, is linked to synaptic dysfunction and neurodegenerative disorders. However, our understanding of how CYLD contributes to the manifestation of neuronal deficits, particularly in the context of ageing, remains limited. Here, we report that CYLD-1 is essential for physiological lifespan in the nematode Caenorhabditis elegans. Neuronal CYLD-1 supports cholinergic neurotransmission and GABAergic synapse integrity, ensuring intact locomotory capacity, as well as learning and memory competence. Specifically, the deubiquitinase activity of CYLD-1 is necessary for upholding cholinergic neurotransmission and lifespan. We further show that CYLD-1 regulates autolysosomal and lysosomal network organisation in neurons and peripheral tissues in vivo. Our work unveils a crucial role of CYLD-1 in optimizing neural activity and behavioural outcomes, to improve organismal fitness and survival.
    DOI:  https://doi.org/10.1038/s41467-026-73966-5
  39. Spectrochim Acta A Mol Biomol Spectrosc. 2026 May 30. pii: S1386-1425(26)00731-6. [Epub ahead of print]362 128160
    Lysosome-targeted near-infrared fluorescent probes for monitoring aβ plaques in vivo and aβ monomers dynamic degradation in vitro.
    Huiyuan Gong, Zhuangqing Li, Yongmei Zhao, Zihua Wang, Wen Luo.
      The aggregation of β-amyloid (Aβ) is a central pathological feature of Alzheimer's disease (AD), with its dynamic changes closely linked to disease progression. Lysosomes play a critical role in the clearance and degradation of Aβ, making them an important focus in AD research. In this study, a series of multifunctional lysosome-targeting near-infrared fluorescent probes based on a dicyanoisophorone scaffold were developed to enable simultaneous targeting of lysosomes and monitoring of Aβ aggregates. All probes effectively localized within cellular lysosomes, with NCM-4 demonstrating the most efficient lysosomal targeting, along with high selectivity, specificity, and strong binding affinity toward Aβ aggregates. Both in vivo imaging and ex vivo brain slice staining confirmed that the probe efficiently crossed the blood-brain barrier and selectively accumulated in the brains of APP/PS1 transgenic mice, allowing clear visualization of Aβ plaques. Furthermore, due to its lysosomal localization, NCM-4 enabled real-time tracking of the internalization of FITC-labeled Aβ monomers (FITC488Aβ) from the extracellular environment into lysosomes. This capability also allowed monitoring of how autophagy modulation, via chloroquine and rapamycin, influences Aβ clearance within lysosomes. Overall, these probes, particularly NCM-4, provide a valuable platform for AD diagnosis and offer powerful tools for studying lysosome-mediated Aβ clearance mechanisms and therapeutic interventions.
    Keywords:  Autophagy; Aβ; Dicyanoisophorone; Lysosomes; Near-infrared
    DOI:  https://doi.org/10.1016/j.saa.2026.128160
  40. bioRxiv. 2026 May 21. pii: 2026.05.19.726221. [Epub ahead of print]
    Live cell imaging reveals paclitaxel-induced lysosome motility and function disruption in DRG neurons.
    Kathleen Cate Domalogdog, Ishwarya Sankaranarayan, Úrzula Franco-Enzástiga, Juliet M Mwirigi, Shani Mai Nguyen, Diana Tavares-Ferreira, Theodore J Price.
      Lysosomal trafficking and homeostasis are biological functions that are pivotal for DRG neurons, given their metabolic demands and extremely long axons. Previous studies indicate that lysosomal signaling is altered in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) and that blocking mitogen activated protein kinase-associated kinase (MNK1/2) signaling can alleviate pain behaviors in CIPN. Here, we investigated lysosome dynamics and lysosome-associated signaling in a mouse model of CIPN induced by paclitaxel (PTX), a chemotherapeutic agent used for various types of cancer. Using spinning disk super-resolution microscope (SPINSR), we demonstrate that PTX treatment in vivo causes reduced lysosome motility observed in vitro. PTX likewise drives the accumulation of Sequestosome 1 (SQSTM1), also known as P62, in cultured mouse DRG neurons, indicating lysosomal dysfunction in DRG neurons. The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, was also upregulated in the nucleus of cultured mouse DRG neurons treated with PTX. In line with this, increased lysosomal-associated membrane protein 1 (LAMP1) expression was observed in PTX-treated mice. Given that our previous work demonstrated PTX treatment increases MNK1/2-eIF4E signaling in DRG neurons, we examined whether MNK1/2 inhibition could rescue lysosomal dysfunction. Treatment with Tomivosertib (eFT508), a potent MNK1/2 inhibitor, restored P62 levels in DRG neurons of PTX-treated mice and reduced TFEB in DRG treated in vitro . To establish translation relevance, we further show that PTX elevates phosphorylated eiF4E (p-eIF4E) in human DRG neurons, and concurrent eFT508 administration attenuates this effect. Collectively, these findings indicated that PTX disrupts lysosome trafficking and biogenesis, and that MNK inhibition with eFT508 restores lysosomal signaling and can serve as a neuroprotective strategy for CIPN.
    DOI:  https://doi.org/10.64898/2026.05.19.726221
  41. Front Endocrinol (Lausanne). 2026 ;17 1726834
    Tumor stage-dependent expression of autophagy proteins in adrenocortical carcinoma.
    Sofia B Oliveira, Diana Sousa, Madalena Costa, Elisabete Rios, Tiago Nunes da Silva, Valeriano Leite, Sofia S Pereira, Duarte Pignatelli.
       Introduction: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor yet heterogeneous prognosis, mostly due to its complex and incompletely understood molecular background. Autophagy is a multi-step catabolic process with a dual role in tumorigenesis, acting either as a tumor suppressor or promoter in a context-dependent manner. Therefore, our aim was to investigate the expression of key proteins involved in different autophagy steps in both adrenocortical adenomas (ACA) and ACC, to further understand the role of autophagy in this type of tumors, particularly its involvement in the pathophysiology of ACC.
    Methods: Autophagy status was evaluated in ACA (n=20) and ACC (n=29) by assessing the expression of autophagy-related protein 5 (ATG5), microtubule associated protein 1 light chain 3 beta (LC3B), and sequestosome 1 (p62/SQSTM1), using immunohistochemistry. Additionally, in vitro experiments, including migration and invasion assays, were conducted in JIL-2266 and H295R cell lines to investigate the impact of autophagic flux inhibition in ACC cell behavior.
    Results: LC3B punctate staining was present in 89% of ACC and 25% of ACA, with significantly higher LC3B expression in ACC compared to ACA (14.81 ± 2.26% vs 2.05 ± 1.00%, p < 0.0001). ACC with ENSAT stage of 1-2 exhibited significantly higher LC3B expression compared to ACC with ENSAT 3-4 (19.17 ± 1.05% vs 12.62 ± 4.00%, p = 0.02). Similarly, non-metastatic ACC showed a significantly higher percentage of LC3B positive cells than metastasized ACC (18.77 ± 3.52% vs 5.83 ± 1.70%, p = 0.004). In vitro, inhibition of autophagy significantly reduced cell migration and invasion in ACC cells. Higher cytoplasmic p62/SQSTM1 levels were found in ACC with advanced disease (ENSAT 3-4 vs ENSAT 1-2: 72.07 ± 3.61% vs 51.33 ± 9.24%, p = 0.02). No significant differences were observed for ATG5.
    Discussion: Our findings indicate a tumor stage-dependent role of autophagy in ACC and show that autophagy may play a role in ACC molecular pathophysiology. A punctate LC3B expression accumulation, associated with less aggressive malignant features, namely absence of metastasis, appears to result from a blockade at the late stages of autophagy. Whereas active autophagy may be associated with a more aggressive cellular phenotype in ACC, particularly by promoting migration and invasion.
    Keywords:  LC3; adrenocortical carcinoma; autophagy; immunohistochemistry; molecular pathophysiology; p62/SQSTM1
    DOI:  https://doi.org/10.3389/fendo.2026.1726834
  42. Neurochem Res. 2026 Jun 01. pii: 181. [Epub ahead of print]51(3):
    Taliglucerase Alfa Reduces Amyloid-β Burden by Restoring Autophagic Pathways in a Neuronal Model of Alzheimer's Disease.
    Çağrı Özkurt, Selma Köse, Çimen Karasu, Arjan Kortholt, Pelin Kelicen-Uğur.
      Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to low-molecular-weight Aβ1-42 oligomer-enriched assemblies (oAβ1-42), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.
    Keywords:  Alzheimer’s disease; Autophagy; Enzyme replacement therapy; Lysosomal storage disorder; Taliglucerase alfa; β-Glucocerebrosidase
    DOI:  https://doi.org/10.1007/s11064-026-04792-w
  43. Commun Biol. 2026 Jun 04.
    Cardiac-derived extracellular vesicles carrying miR-4433b-3p accelerate cognitive decline and brain aging by suppressing TP53INP2-mediated neuronal autophagy in mice.
    Qian Cheng, Zhikang Cui, Shuyi Yu, Guixia Li, Hang Chen, Qian Yu, Jialin Han, Shuang Wu, Yan Jin, Yunshan Wang, Ming Li, Zhiming Lu.
      Brain aging is not an independent process, yet how systemic aging drives neural decline remains unclear. Here, we identified a circulating miR-4433b-3p, packaged within extracellular vesicles (EVs), as a trans-organ effector bridging cardiac aging with central nervous system (CNS) decline. Small RNA sequencing and human cohort validation revealed selective enrichment of miR-4433b-3p in aged plasma EVs (Op-EVs), correlating with blood biomarkers of brain aging. Source tracing in mice identified the aged heart as the major origin of miR-4433b-3p-laden EVs. Functionally, aged cardiac EVs (Oc-EVs) accumulated in the hippocampus, impaired memory and induced neuronal senescence. Mechanistically, miR-4433b-3p suppressed TP53INP2, a facilitator of autophagic flux, leading to disrupted autophagosome maturation. Restoring TP53INP2 or inhibiting miR-4433b-3p rescued neuronal autophagy and improved cognition. Collectively, these findings uncover a heart-brain axis by EV-mediated miRNA signaling, positioning cardiac EV-miR-4433b-3p as a circulating biomarker and potential therapeutic target for age-related cognitive decline.
    DOI:  https://doi.org/10.1038/s42003-026-10332-7
  44. Front Aging. 2026 ;7 1791853
    Dietary pyrroloquinoline quinone and spermidine in healthy longevity: targeting the hallmarks of aging.
    Tomoe Numaguchi, Mai Nakamura, Tomoyo Koshizawa, Nur Syafiqah Mohamad Ishak, Katsuyuki Hashimoto.
       Background: Aging is a multifaceted biological process driven by interconnected cellular and molecular hallmarks. As geroscience increasingly prioritizes healthspan over lifespan, nutritional interventions targeting multiple aging mechanisms have gained attention as accessible strategies to mitigate age-related functional decline.
    Objective: This mini review synthesizes recent evidence on how the bioactivities of two food-derived geroprotective compounds, pyrroloquinoline quinone (PQQ) and spermidine (SPD), intersect with the hallmarks of aging and their distinct and overlapping roles in maintaining cellular homeostasis.
    Findings: PQQ primarily functions as a mitochondrial and redox regulator, enhancing mitochondrial biogenesis and bioenergetic capacity through the AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathways. In contrast, SPD acts as a key regulator of cellular quality control by inducing macroautophagy and preserving proteostasis, largely through modulation of histone and autophagy-related protein acetylation. These complementary mechanisms converge on several key hallmarks of aging, including genomic instability, deregulated nutrient sensing, mitochondrial dysfunction, and chronic inflammation.
    Conclusion: The anti-aging mechanisms of PQQ and SPD originate from distinct upstream biochemical processes but converge on shared signaling hubs, including the AMPK/SIRT1 axis and autophagy-related networks. This convergence suggests a coordinated network-level complementarity that may offer a more robust intervention against age-related decline than targeting independent pathways alone.
    Keywords:  anti-aging; autophagy; longevity; mitochondria; nutritional intervention; pyrroloquinoline quinone; spermidine
    DOI:  https://doi.org/10.3389/fragi.2026.1791853
  45. Environ Int. 2026 May 22. pii: S0160-4120(26)00283-7. [Epub ahead of print]213 110325
    FOXA1 protects against PM2.5-induced chronic lung injury via MARCHF8-dependent mitophagy inhibition.
    Xu Wu, Lingfeng Liu, Dafei Wei, Rongfang Tu, Fang Zhou, Jin Xu, Lin Chen, Sha Liu.
      The function and mechanism of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) in fine particulate matter (PM2.5)-induced lung injury remain unknown. The effect of MARCHF8 overexpression on PM2.5-induced lung injury in mice was evaluated through lung pathology, apoptosis, and inflammation. The function of MARCHF8 was studied using HBE135-E6E7 and BEAS-2B cells stimulated by PM2.5. Mitochondrial autophagy was evaluated by the protein levels, mt-Keima ratio, MMP, mtROS, and LC3/PINK1/Parkin. The relationship of the FOXA1/MARCHF8/HK2 axis was detected by ChIP, Co-IP and cycloheximide. MARCHF8 expression decreased in PM2.5-exposed mouse lungs, HBE135-E6E7 and BEAS-2B cells, and COPD patients. Overexpressing MARCHF8 reduced PM2.5-induced cellular damage by inhibiting PINK1/Parkin-mediated mitophagy. Mechanistically, FOXA1 overexpression boosted MARCHF8 transcription. MARCHF8 promoted HK2 degradation by catalyzing k48-linked ubiquitination at the K763 site, leading to mitophagy inhibition by obstructing PINK1/Parkin recruitment. Furthermore, FOXA1 alleviated PM2.5-induced lung injury by inhibiting mitophagy via the MARCHF8/HK2/Parkin axis, and HK2 overexpression counteracted the protection against PM2.5-induced cytotoxicity provided by MARCHF8 or FOXA1. Meanwhile, the correlation between FOXA1, MARCHF8, and HK2 was validated in clinical samples of COPD patients. In conclusion, FOXA1 overexpression mitigates PM2.5-induced lung injury by suppressing mitophagy via the MARCHF8/HK2/Parkin axis, which may be a promising therapeutic strategy in the future.
    Keywords:  FOXA1; HK2; MARCHF8; Mitophagy; PINK1/Parkin; PM2.5
    DOI:  https://doi.org/10.1016/j.envint.2026.110325
  46. Curr Med Chem. 2026 May 20.
    Mitophagy in Pulmonary Fibrosis: Molecular Interactions, Hypoxia Interactions, and Therapeutic Strategies.
    Xuelin Zhang, Lingjie Wang, Hongwang Yan, Yizhao Chen, Chunya He.
      Mitophagy plays a central role in the pathogenesis of Pulmonary Fibrosis (PF). Defective mitophagy leads to the accumulation of damaged mitochondria, resulting in bursts of mitochondrial Reactive Oxygen Species (mtROS), ferroptosis, and cellular senescence. These processes collectively promote aberrant fibroblast activation and excessive extracellular matrix deposition. This review systematically explored the molecular regulatory network of mitophagy in PF and its interactions with hypoxia-responsive pathways. These abnormalities create a vicious cycle of autophagy inhibition and fibrosis activation, which accelerates disease progression. Regarding therapeutic strategies, various small-molecule drugs and natural compounds have shown anti-fibrotic potential by activating mitophagy, alleviating oxidative stress, and delaying cellular senescence. Emerging technologies, such as gene therapy, nanocarriers, and combination therapies, are providing additional avenues for clinical translation. However, targeting mitophagy still faces challenges, including cell type specificity, dynamic conversion thresholds, and delivery efficiency. Future efforts will require integrating single-cell multi-omics and artificial intelligence approaches to develop spatiotemporally precise intervention systems for personalized, precision treatment of PF.
    Keywords:  ECM.; Pulmonary fibrosis; lung tissue; mitochondria; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.2174/0109298673451634260305040940
  47. bioRxiv. 2026 May 21. pii: 2026.05.20.726708. [Epub ahead of print]
    Diet-dependent sleep modulation by the Drosophila amino acid transporter ANIDRA.
    Ratna Chaturvedi, Rita R Fagan, Chenghao Chen, Tobias Stork, Marc R Freeman, Haley E Melikian, Patrick Emery.
      Sleep is a conserved animal behavior necessary for survival. It is under tight circadian and homeostatic control, and modulated by diet. Here, we identify the amino acid transporter ANIDRA (ANID) as an important sleep regulator in Drosophila . Flies lacking ANID show decreased and poorly consolidated daytime and nighttime sleep. Contrary to wild-type controls, anid mutant flies are unable to adjust their sleep to their diet, behaving as if they were constantly on a complete diet rich in amino acids. ANID is expressed in ensheathing and cortex glia, where it inhibits mTOR activity in a diet-dependent manner. Moreover, pharmacological inhibition of mTOR attenuates the anid mutant sleep phenotypes. Interestingly, DH44-expressing brain neurons, which promote arousal and sense amino acids, are constantly active in ANID's absence. We therefore propose that ANID mediates detection of dietary amino acids by ensheathing and cortex glia to regulate the activity of arousal-promoting neurons.
    DOI:  https://doi.org/10.64898/2026.05.20.726708
  48. Cell Signal. 2026 Jun 02. pii: S0898-6568(26)00283-4. [Epub ahead of print] 112630
    Role of homocysteine in renal tubular epithelial-mesenchymal transition: N-homocysteinylation of β-catenin impairs FUNDC1-dependent autophagy and mitochondrial quality control.
    Yanping Lei, Fang Guo, Hui Sun, Ji Huang, Yue Zhao.
      Given the nephrotoxicity of hyperhomocysteinemia and the key role of mitophagy in the homeostasis of kidney, this study investigated the β-catenin/FUNDC1/mitochondrial quality control axis to elucidate the mechanisms underlying homocysteine-induced renal tubular fibrosis. A mouse model of hyperhomocysteinemia was established via continuous supplementation of homocysteine. Western blot quantified key proteins associated with autophagy (FUNDC1, LC3, p62), fibrosis (fibronectin, α-SMA, Snail1), β-catenin signaling, and kidney injury (KIM-1). Immunostaining assessed renal spatial distribution of β-catenin, FUNDC1, α-SMA, and fibronectin, while transmission electron microscopy visualized mitochondrial ultrastructural changes. ChIP and dual-luciferase reporter assays verified the transcriptional target. Meanwhile, IP combined with mass spectrometry (MS), molecular modeling, and site-directed mutagenesis identified the modification site. β-catenin signaling inhibition by homocysteine resulted in diminished FUNDC1 expression within renal tubular epithelial cells, simultaneously suppressing autophagy and facilitating renal tubular fibrosis. β-catenin overexpression enhanced FUNDC1 expression, thereby rescuing homocysteine-suppressed autophagy and effectively mitigating renal tubular epithelial-mesenchymal transition (EMT). FUNDC1 overexpression mitigated homocysteine-induced cellular stress, further enhanced autophagy and mitochondrial quality control, and alleviated renal tubular EMT. Further, dual-luciferase reporter assays and ChIP confirmed FUNDC1 as a β-catenin transcriptional target. IP combined with MS, molecular modeling, and site-directed mutagenesis experiments revealed that homocysteine induced N-homocysteinylation of β-catenin at Lys49, which remodeled β-catenin's local structure to promote Ser45 phosphorylation and subsequent β-catenin degradation. Conclusively, homocysteine induces N-homocysteinylation of β-catenin at Lys49 to promote its degradation, thereby inhibiting β-catenin-mediated transcriptional activation of FUNDC1, disrupting autophagy and mitochondrial quality control, and ultimately inducing renal tubular EMT.
    Keywords:  Autophagy; EMT; FUNDC1; Homocysteine; N-homocysteinylation; β-Catenin
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112630
  49. Biochem Pharmacol. 2026 Jun 01. pii: S0006-2952(26)00454-5. [Epub ahead of print] 118119
    ACE2 ameliorates DOX-induced cardiotoxicity by suppressing excessive autophagy via the AMPK/mTOR signaling pathway.
    Jingjing Gong, Qingqing Li, Mei Lin, Changsheng Xu, Dajun Chai, Jinxiu Lin, Feng Peng.
      Doxorubicin (DOX) cardiotoxicity involves dysregulated autophagy, yet the role of ACE2 in this process remains unclear. We aimed to determine if ACE2 protects against DOX-induced injury by modulating the AMPK/mTOR-autophagy axis. DOX-induced cardiotoxicity was established in mice and primary cardiomyocytes. The effects of modulating ACE2 and mTOR signaling were investigated using the agonist Diminazene Aceturate (DIZE), inhibitor MLN-4760, activator MHY1485 (MHY), and inhibitor Rapamycin (Rapa). Cardiac injury, apoptosis, autophagy, and key molecules in the RAS and AMPK/mTOR pathways were evaluated. DOX induced cardiac dysfunction, apoptosis, and excessive autophagy, accompanied by ACE2 downregulation, AMPK activation, and mTOR inhibition. ACE2 activation via DIZE reversed these pathologies both in vivo and in vitro. Mechanistically, the cardioprotective effects of DIZE were mimicked by mTOR activation and, importantly, abolished by mTOR inhibition with Rapamycin. Our findings demonstrate that ACE2 protects against DOX-induced cardiotoxicity by suppressing excessive autophagy. This effect is causally dependent on its ability to inhibit AMPK and activate mTOR signaling. Thus, targeting the ACE2-mTOR axis represents a promising therapeutic strategy to mitigate DOX cardiotoxicity.
    Keywords:  ACE2; AMPK/mTOR pathway; Autophagy; Cardiotoxicity; Doxorubicin
    DOI:  https://doi.org/10.1016/j.bcp.2026.118119
  50. Signal Transduct Target Ther. 2026 Jun 04. pii: 216. [Epub ahead of print]11(1):
    Transcriptional and epigenetic regulation of autophagy: mechanisms, disease relevance and therapeutic opportunities.
    Jieun Seo, Seo-Young Park, Dong Chul Lee, Wonbeak Yoo, Yong Ryoul Yang, Hwi Won Seo, Jong Lyul Park, Jae-Yeol Joo, Kyung Chan Park, Sangwon Byun.
      Autophagy is a tightly regulated catabolic process that is essential for cellular homeostasis, stress adaptation, and metabolic balance. Its dysregulation has been implicated in a wide range of diseases, including cancer, neurodegenerative disorders, metabolic syndromes, muscular diseases, and infections. Recent studies have revealed the central roles of transcription factors, including TFEB, FOXO family members, p53, and NF-κB, in orchestrating autophagy through their direct regulation of lysosome-related genes. These factors often interact with epigenetic regulators such as histone acetyltransferases, deacetylases, and methyltransferases, which fine-tune chromatin accessibility and transcriptional output. Dysregulation of these pathways leads to aberrant autophagy and contributes to pathogenesis. Emerging therapeutic strategies targeting these transcriptional and epigenetic regulators have shown promise in preclinical and clinical settings, although challenges remain owing to the context-specific roles of autophagy in promoting either cell survival or cell death or contributing to protein aggregation and metabolic imbalance, depending on the disease. Clinical trials with autophagy modulators, including mTOR inhibitors, HDAC inhibitors, SIRT1 activators, and TFEB agonists, have yielded variable outcomes, emphasizing the need for precision medicine approaches. Advances in nanomedicine and biomaterials provide innovative delivery platforms that increase the specificity, bioavailability, and tissue targeting ability of autophagy-targeting agents. This review provides a comprehensive and detailed synthesis of how transcriptional and epigenetic regulators control autophagy across physiological and pathological contexts. In addition, we discuss therapeutic efforts, challenges in clinical translation, and future directions, including biomarker discovery, combinatorial treatment strategies, and targeted delivery systems, to enable more effective modulation of autophagy in disease.
    DOI:  https://doi.org/10.1038/s41392-026-02688-3
  51. Cell Death Dis. 2026 May 30.
    CLN7 suppression induces apoptosis via mTOR-regulated and chaperone-mediated autophagy in myeloid leukemia cells.
    Miaomiao Wu, Hui Li, Sujun Li, Qianwen Xu, Yijing Liao, Lili Qu, Chunlei Cang, Xingbing Wang.
      Refractory disease and relapse continue to impede effective treatment of myeloid leukemia, despite substantial progress in therapeutic approaches. Emerging evidence implicates lysosomal ion channels in the regulation of cell death pathways, highlighting these channels as viable targets for therapeutic intervention. This study identified elevated expression of the lysosomal ion channel CLN7 in myeloid leukemia cells. Suppression of CLN7 triggered apoptosis, inhibited cellular proliferation, and markedly reduced the abundance of oncogenic proteins. Mechanistically, CLN7 inhibition promoted nuclear translocation of TFEB by downregulating mTOR signaling, thereby enhancing lysosomal biogenesis and macroautophagy. Notably, CLN7 suppression selectively accelerated chaperone-mediated autophagic degradation of BCR-ABL through cathepsin B (CTSB) upregulation. In addition, inhibition of CLN7 induced autophagy-mediated apoptosis, which led to significant impairment of leukemogenic potential. Co-treatment with chemotherapeutic agents and CLN7 suppression enhanced therapeutic efficacy in myeloid leukemia cells. Finally, suppression of CLN7 markedly reduced tumor growth in human xenograft models without compromising normal hematopoietic function. These findings establish CLN7 as a critical regulator of leukemic cell survival, representing a promising therapeutic target for myeloid leukemia.
    DOI:  https://doi.org/10.1038/s41419-026-08936-2
  52. Bone. 2026 Jun 02. pii: S8756-3282(26)00184-5. [Epub ahead of print]211 117958
    Osteogenic promotion by naringin through the PI3K/AKT/mTOR pathway-mediated activation of autophagy and inhibition of apoptosis.
    Yubo Cui, Guisong Yu, Dian Li, Xing Fu, Zhijun Yang, Wenlong Yang, Fengyun Yang.
      Osteoporosis is a common age-related metabolic bone disease closely associated with osteoblast dysfunction, abnormal apoptosis, and dysregulated autophagy. Naringin, a dihydroflavonoid compound mainly found in citrus fruits and various traditional Chinese medicinal herbs (e.g., Aurantii Fructus Immaturus and Rhizoma Drynariae), exhibits potential anti-aging and osteoprotective effects; however, its specific mechanism requires systematic elucidation. Network pharmacology analysis revealed that the core targets of naringin are significantly enriched in the PI3K/AKT signaling pathway, as well as pathways related to apoptosis and autophagy. Subsequent in vitro experiments demonstrated that naringin promotes osteoblast proliferation, differentiation, and mineralization; upregulates the expression of osteogenic markers; activates protective autophagy; and inhibits apoptosis. By employing the autophagy inhibitor 3-MA and the PI3K/AKT agonist 740Y-P to modulate PI3K/AKT/mTOR-mediated autophagy, we confirmed that the anti-apoptotic effect of naringin is dependent on the activation of autophagy. In vivo, naringin administration inhibited the excessive activation of the PI3K/AKT/mTOR pathway, enhanced autophagy, suppressed excessive apoptosis, ameliorated bone microarchitecture, and increased bone mineral density in ovariectomized mice. Our findings elucidate the mechanism by which naringin exerts its anti-osteoporotic effects through regulating the balance between autophagy and apoptosis, thereby providing a theoretical basis for developing naringin-based anti-aging strategies for bone protection.
    Keywords:  Apoptosis; Autophagy; Naringin; Osteoporosis
    DOI:  https://doi.org/10.1016/j.bone.2026.117958
  53. Mol Biol Cell. 2026 Jun 03. mbcE26040158
    Beyond Transport: Lysosomal solute carriers as orchestrators of immune signaling.
    Daniel J Netting, Sergio Grinstein, Adriana R Mantegazza.
      Solute carriers (SLCs) are the most abundant family of transmembrane transporters. They transport solutes such as amino acids, nucleosides and ions across membranes, regulating their cytosolic availability and maintaining homeostasis within organelles. While their expression is ubiquitous, SLCs play unique roles in immune cells, where endo-lysosomes and phagosomes function as sites of pathogen detection and destruction. Much of this process is carefully orchestrated by lysosomal SLCs that transport pathogen-derived patterns to the cytosol for detection, transmit danger signals to promote microbial clearance, and regulate autophagy to resolve inflammation. In this Perspective, we discuss these alternative functions of lysosomal SLCs and discuss the possibility that they also serve as innate immune sensors.
    DOI:  https://doi.org/10.1091/mbc.E26-04-0158
  54. Redox Biol. 2026 May 30. pii: S2213-2317(26)00240-5. [Epub ahead of print]95 104242
    CHK1 activates mitophagy to attenuate cardiac aging via inhibiting AHSA1-ubiquitination.
    Peng Jing, Liu-Hua Zhou, Shu-Xuan Chen, Jia-Yi Chen, Ling-Feng Gu, Tong-Tong Yang, Si-Bo Wang, Chong Du, Yi-Xi Chen, Qi-Ming Wang, Lian-Sheng Wang, Hao Wang.
      With the acceleration of global population aging, the progressive deterioration of cardiac structure and function has become a critical determinant of cardiovascular health, presenting a significant public health challenge. Checkpoint kinase 1 (CHK1), a key cell cycle checkpoint protein, plays an essential role in various biological processes by mediating signaling cascades. While CHK1 has been shown to be important for heart regeneration, its role in the aging process of the heart remains unclear. In this study, we investigated the alterations in CHK1 expression in aging hearts and elucidated the underlying regulatory mechanisms. In both in vivo and in vitro models, CHK1 expression was significantly downregulated during aging. To assess its functional role, we generated cardiomyocyte-specific CHK1 overexpression and knockout mice and compared their cardiac performance. We found that CHK1 overexpression alleviated age-associated cardiac dysfunction, while CHK1 knockout worsened cardiac function in aged mice. Furthermore, CHK1 overexpression significantly attenuated doxorubicin (DOX)-induced acutely senescence in adult mouse cardiomyocytes (AMCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic studies revealed that CHK1 overexpression delayed cardiac aging by activating heat shock protein 90 (HSP90)-mediated mitophagy. Immunoprecipitation and mass spectrometry (IP-MS) analyses demonstrated that CHK1 directly interacts with the activator of HSP90 ATPase homolog 1 (AHSA1), thereby suppressing TRIM8-mediated ubiquitination and degradation, facilitating AHSA1-HSP90 complex formation, and enhancing HSP90 ATPase activity. Overall, our results suggest that CHK1 overexpression activates mitophagy via the AHSA1-HSP90 pathway to mitigate cardiac aging. This study highlights the critical role of CHK1 in cardiac aging and proposes a potential therapeutic strategy for aging-associated cardiomyopathy and heart failure.
    Keywords:  AHSA1; CHK1; Cardiac aging; HSP90; Mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2026.104242
  55. Autophagy. 2026 May 31. 1-3
    AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer's disease.
    Yu Dong, Xianglu Xiao, Xu-Xu Zhuang, Wenfan Wu, Evandro F Fang, Guang Yang, Zhangming Niu, Jia-Hong Lu.
      Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.
    Keywords:  Alzheimer’s disease; artificial intelligence; autophagy; blood-brain barrier; drug discovery
    DOI:  https://doi.org/10.1080/15548627.2026.2679639
  56. bioRxiv. 2026 May 27. pii: 2026.05.22.727304. [Epub ahead of print]
    Atg8 orchestrates stress-responsive chromatin programs across immunity and metabolism.
    Kevin P Kelly, Navyashree A Ramesh, Sunidhi Ranganathan, Aditi Madan, Shannon Marschall, Robert L Unckless, Akhila Rajan.
      Organisms must coordinate transcriptional responses to immune and metabolic stress, often within the same tissue. In Drosophila and mammals, adipose tissue integrates these signals by mounting antimicrobial defense during acute infection and remodeling lipid metabolism under chronic nutrient surplus. How one cell-biological system supports both functions, and through what molecular machinery, remains incompletely understood. Atg8/LC3, classically defined by canonical autophagy, has emerging non-canonical roles in nuclear gene regulation, raising the possibility that it contributes to stress-coordinated transcription beyond cargo turnover. Using unbiased CUT&RUN in adult Drosophila nuclei, we find that endogenous Atg8 exhibits broad chromatin occupancy at immune, metabolic, and autophagy loci, and accumulates in nuclei under prolonged high-sugar diet (HSD) and acute Gram-positive infection. We identify two conserved Atg8-interacting motifs (AIMs) within the Rel homology domain of NF-κB/Dif. Flies carrying CRISPR-engineered AIM-mutant Dif are highly susceptible to both infection and chronic HSD, establishing a physiological requirement for intact Dif AIMs. AIM-mutant Dif shows impaired infection-induced nuclear accumulation, suggesting that Atg8 contributes to both Dif cytoplasmic-to-nuclear shuttling and nuclear function. Unbiased comparison of Atg8 chromatin occupancy across HSD and infection further reveals shared and divergent motif grammar, positioning Atg8 as a stress-responsive chromatin cofactor for immune and metabolic transcription. Together, these findings expand the functional landscape of Atg8/LC3 beyond canonical autophagy and reveal that autophagy machinery contributes to stress-specific transcriptional complex assembly. AIM/LIR-mediated interactions, exemplified by Dif, represent one such interface, while additional mechanisms likely underlie Atg8's broader chromatin engagement at loci enriched for transcription factor motifs whose cognate factors lack known AIM/LIRs. We propose that Atg8/LC3-mediated coordination of immune and metabolic transcription is a general principle by which cells integrate diverse stress signals, with implications for obesity, chronic inflammation, and other disease states in which immune and metabolic dysregulation converge.
    GRAPHICAL ABSTRACT: Stress drives Atg8 into nuclei, where it occupies immune and metabolic chromatin.Two conserved AIMs in NF-κB/Dif bind Atg8 and enable Dif nuclear entry.AIM-mutant Dif flies are highly susceptible to infection and chronic high-sugar diet.Atg8 occupies stress-related motifs on prolonged HSD and acute infection.
    DOI:  https://doi.org/10.64898/2026.05.22.727304
  57. Annu Rev Nutr. 2026 Jun 02.
    Mechanisms of NAD+ Homeostasis in Aging and Disease.
    Melanie R McReynolds.
      Aging is the greatest risk factor for many of society's most prevalent diseases, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders. A common thread underlying these conditions is the disruption of cellular and metabolic homeostasis. All hallmarks of aging converge on mechanisms that disrupt how cells communicate, interact, and coordinate their functions. Emerging studies have implicated diminished NAD+ levels as a contributor to several hallmarks of aging, underscoring their regulatory role in age-dependent decline. While it remains unclear whether aging drives metabolic decline or if metabolic dysregulation accelerates aging-or both-a growing body of evidence suggests that NAD+ metabolism may be a key link between disrupted communication and metabolic dysfunction. This review integrates current insights into how NAD+ metabolism and signaling influence cellular and organismal aging, emphasizing the nutritional factors that modulate these processes. Together, these perspectives position NAD+ as a unifying framework linking nutrition, metabolic resilience, and the mechanisms of healthy aging and disease.
    DOI:  https://doi.org/10.1146/annurev-nutr-112525-013335
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