bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–06–14
sixty-one papers selected by
Viktor Korolchuk, Newcastle University
  1. STING1 senses mitochondrial damage to promote mitophagy.
  2. Glycophagy: A selective autophagy pathway for glycogen degradation.
  3. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  4. Mitophagy: an emerging therapeutic target in mitochondrial diseases.
  5. Synphilin-1 mitigates autophagy dysfunction, modulates ubiquitinated protein aggregation, and promotes cell survival during proteotoxic stress.
  6. Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.
  7. Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
  8. Autophagy and primary cilium: A dynamic duo in cellular homeostasis and disease.
  9. APOE4-Expressing Astrocytes Exhibit Parkinson's Disease-Related Pathology.
  10. The ESCRT-0 protein HRS regulates hepatocellular lipid droplet catabolism.
  11. Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
  12. Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
  13. Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.
  14. The autophagy protein ATG-9 promotes aversive learning in Caenorhabditis elegans through trafficking neuropeptide receptors.
  15. Metformin activates AMPK-TFEB signaling to restore lysosomal and mitochondrial homeostasis and suppress EMT in oxidative stress-injured retinal pigment epithelium.
  16. VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.
  17. Lipid Codes and Lipid-Binding Proteins as Central Regulators of Autophagy.
  18. The Role of PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury: A Review of Recent Advances.
  19. Disruption to TFEB signaling and autophagy in newly formed oligodendrocytes leads to aberrant generation of CNS myelin.
  20. Atg23 interacts with both the N- and C-termini of Atg9 via a hydrophobic binding pocket.
  21. E-cigarette aerosols induce the hydrolysis of lysosomal glycerophospholipids through PLA2G4A activation initiated by nicotine binding to CHRNA3/α3 nAchr in airway epithelial cells.
  22. Restoring BECN1-mediated autophagy mitigates acute lung injury caused by zinc oxide nanoparticles.
  23. MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
  24. Unraveling the interplay of glycolysis, lactylation, and autophagy.
  25. SEC14L2 couples chaperone-mediated autophagy to microtubule stability by targeting Stathmin 1.
  26. The Legionella pneumophila type IVb secretion system effector BinA subverts amino acid transport to sensitize TORC1 signaling in macrophages.
  27. Dysregulation of autophagosome-mitochondria contacts contributes to autophagy dysfunction and neurodegeneration in tauopathy.
  28. Contradictory Effects on Hepatocytes in ASMD.
  29. PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.
  30. Robust analytical methods for bis(monoacylglycero)phosphate profiling in health and disease.
  31. Autophagy in VZV infection: To degrade, or to deliver?
  32. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  33. The purinergic receptor P2X4R stimulates macro-autophagy with impact on lipid droplet size in fatty liver.
  34. Role of autophagy in adipose tissue: Implications for metabolic health.
  35. Autophagy and type 2 diabetes: Bridging the gap in metabolic health.
  36. HKDC1 contributes to aberrant lysosome-mitochondria contact in Niemann-Pick disease type C.
  37. Targeting the RNF31-TFEB-NLRP3 Axis With a Curcumin Analog to Restore Autophagy and Alleviate Intestinal Inflammation.
  38. Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.
  39. Targeted degradation of intracellular organelles: Strategies and implications.
  40. From lipid overload to autophagy collapse: how lipid dysregulation drives chronic inflammation and metabolic disease.
  41. HSPA1-regulated mitophagy-necroptosis crosstalk determines the fate of brain microvascular endothelial cells after cerebral ischemia.
  42. UBC/UBA52 silencing restores PINK1-Parkin-mediated mitochondrial autophagy in allergic rhinitis.
  43. LDL receptor-mediated lipoprotein uptake fuels human CD4+ T cell polarization toward a c-MAF/IL-10- and FOXP3-driven phenotype.
  44. IRF-1 Links Cytoskeletal Contraction With Inflammatory Response in mTOR-Inhibited Endothelial Cells.
  45. Dynorphin B Promotes Autophagy and Cytotoxicity in Thyroid Cancer Cells via the mTORC1-TFE3 Axis.
  46. A peptide-induced regression of low-grade malignant breast tumor via activation of autophagy in breast cancer cells.
  47. Ceramide kinase/ceramide 1-phosphate signaling regulates LC3B expression and autophagosome formation.
  48. Discovery of a snail hibernation-inducer offering hibernation-like cardioprotection through metabolic rewiring and autophagy in mice.
  49. Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
  50. Cleavage of TOM1 by the SARS-CoV-2 main protease NSP5 prevents autophagic degradation of viral envelope.
  51. RNF26 Bridges ER Stress and Autophagy in the Clearance of MERS Envelope protein.
  52. Canonical autophagy remains inactive in induced pluripotent stem cells and neuronal progenitor cells following DNA damage induced by BPDE or etoposide.
  53. Fetal growth is driven by a bimodal fetal beta cell response and reshaped by a ketogenic diet in a mouse model of maternal diabetes.
  54. Selective HDAC6 inhibition perturbs autophagy and enhances integrated stress response-mediated immunogenic apoptosis in chronic myeloid leukemia.
  55. Cell stress and death liberate the autophagy-inhibitory tissue stress hormone DBI/ACBP into the circulation.
  56. Galectin-1 exacerbates hepatic steatosis by impairing autophagy via interaction with FIP200.
  57. Lysine acetyltransferase 8-mediated histone acetylation, regulated by GBA1, is associated with lysosomal function related to α-Synuclein pathology.
  58. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  59. Vacuole pH loss triggers ESCRT-dependent plasma membrane remodeling to prevent amino acid toxicity.
  60. A protective role for APP in nuclear waste clearance via lysosomal exocytosis.
  61. Mitophagy-mediated immune evasion: Shared strategies of pathogens.
  1. Autophagy. 2026 Jun 13.
    STING1 senses mitochondrial damage to promote mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.
      The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
    Keywords:  Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2689463
  2. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00120-0. [Epub ahead of print]403 123-143
    Glycophagy: A selective autophagy pathway for glycogen degradation.
    Pascual Sanz, Maria Adelaida Garcia-Gimeno.
      Selective autophagy is the process by which specific cellular components are degraded through cargo receptors that recognize target molecules for lysosomal degradation. Among these pathways, glycophagy is a form of ubiquitin-independent selective autophagy that specifically targets glycogen for degradation. In this review, we discuss the molecular components involved in glycophagy, with a particular focus on starch-binding domain-containing protein 1 (STBD1), which functions as a selective autophagy receptor by recognizing glycogen and facilitating its recruitment to autophagosomes. We also examine the physiological and pathological roles of glycophagy, as well as potential therapeutic strategies for targeting this pathway in disease. Finally, we highlight outstanding questions and future directions in this emerging field.
    Keywords:  Autophagosome; Glycophagy; Lysosome; STBD1 receptor; Selective autophagy
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.014
  3. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  4. Biochem J. 2026 Jul 08. 483(7): 1193-1220
    Mitophagy: an emerging therapeutic target in mitochondrial diseases.
    Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.
    Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins
    DOI:  https://doi.org/10.1042/BCJ20260161
  5. bioRxiv. 2026 Jun 02. pii: 2026.05.31.729136. [Epub ahead of print]
    Synphilin-1 mitigates autophagy dysfunction, modulates ubiquitinated protein aggregation, and promotes cell survival during proteotoxic stress.
    Nadine M Lebek, Kenneth G Campellone.
      The decline of cellular proteostasis is a hallmark of aging and key contributor to neurodegenerative diseases. Protein turnover is controlled by the ubiquitin-proteasome and autophagosome-lysosome systems, but how degradation is coordinated when one of these pathways is compromised is not well understood. To study the regulation of proteostasis, we utilized human fibroblasts with targeted knockouts of the cytoskeletal factors WHAMM and JMY, which control multiple steps in autophagy. We found that cells lacking both WHAMM and JMY accumulated numerous intense foci of ubiquitinated proteins when exposed to proteotoxic stress and relied on proteasomes to clear the foci when the stressor was removed. RNA-seq and immunoblotting revealed that WHAMM/JMY knockout cells increased their expression of Synphilin-1, an α-synuclein-interacting protein implicated in Parkinson's Disease. In WHAMM/JMY knockout cells that upregulated endogenous Synphilin-1, and in cell lines engineered to overexpress mCherry-Synphilin-1, ubiquitinated proteins were present in structures containing both Synphilin-1 and proteasomes. RNAi-mediated depletion of Synphilin-1 caused a buildup of ubiquitinated proteins and the ubiquitin-binding adaptor protein SQSTM1/p62, while decreasing cell survival in response to proteotoxic stress. These data suggest that Synphilin-1 plays a pro-survival role in cells with impaired autophagy and functions in the distribution of ubiquitinated cargo during proteasomal degradation.
    DOI:  https://doi.org/10.64898/2026.05.31.729136
  6. Sci Adv. 2026 Jun 12. 12(24): eaee9856
    Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.
    Shuliang Chen, Subhrajit Banerjee, Dongmei Liu, Kamal Kumar, Christopher J Obara, Peter Novick, William A Prinz, Susan Ferro-Novick.
      During cell stress, endoplasmic reticulum autophagy (ER-phagy) receptors remodel the ER by sequestering membrane proteins (cargo) into autophagosomes for degradation. The conserved ER-phagy receptor, Atg40, contains a motif that binds to Atg8 and a reticulon homology domain that is needed for vacuolar/lysosomal delivery. Cargo capture, however, requires the Atg40 binding partner Lst1/SEC24C. To address whether lipids regulate cargo capture during ER-phagy, we analyzed autophagy in neutral lipid-deficient cells. Unexpectedly, we found that Atg40 was delivered to the vacuole in autophagosomes without Lst1/SEC24C or cargo in mutant cells. Lipidomic analysis revealed changes in the ratio of phosphatidylethanolamine to phosphatidylcholine in the neutral lipid-deficient cells that are predicted to alter ER membrane bendability. Our findings imply that phospholipids control cargo sequestration by regulating receptor-cargo coupling at autophagic sites.
    DOI:  https://doi.org/10.1126/sciadv.aee9856
  7. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
    Shalini Singh, Anisha Sharma, Ravi Kumar Rajan, Manodeep Chakraborty, Ananya Bhattacharjee.
       INTRODUCTION: Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD). PINK1-Parkin-mediated mitophagy is a quality-control system for mitochondria that protects neurons by getting rid of damaged mitochondria. The OMA1-DELE1-HRI axis has recently been recognized as a vital regulatory checkpoint that limits excessive mitophagy and prevents metabolic failure during mitochondrial stress. The aim of this review is to analyze the mechanistic interplay between the PINK1-Parkin pathway and the OMA1-DELE1-HRI signaling axis. This study aims to synthesize current research on the influence of the stress-response pathway on the initiation of mitophagy, maintenance of mitochondrial homeostasis, and neuronal survival in PD.
    METHODS: A comprehensive literature review was conducted of molecular, genetic, and pharmacological studies on OMA1, DELE1, and HRI. A thorough analysis of data from kinome-wide screening assays, genetic knockdown experiments, multi-omics profiling, and structural biology studies was performed to elucidate the regulatory interactions between HRI and PINK1 under mitochondrial stress conditions.
    RESULT: The OMA1-DELE1-HRI pathway stops PINK1 from being stable by controlling how mitochondria make proteins and how they respond to stress. This inhibition serves as a metabolic safeguard that regulates mitophagy levels, preventing harmful overactivation. HRI seems to change PINK1-dependent mitophagy while having little effect on other pathways that clear things at the same time. This suggests that HRI has different substrate preferences and signaling specificity.
    DISCUSSION: The OMA1-DELE1-HRI axis is an important negative regulator of mitophagy that PINK1 and Parkin mediate. It stops too much mitochondrial clearance and metabolic failure in Parkinson's disease. This mechanism preserves bioenergetic homeostasis and promotes neuronal survival, suggesting that HRI is a promising therapeutic target. Inhibitors like ISRIB or heme mimetics may selectively restore mitophagy, thereby enhancing neuroprotection and enabling precision therapies guided by biomarkers such as phosphorylated eIF2.
    CONCLUSION: The OMA1-DELE1-HRI axis is a distinctive regulatory mechanism for mitochondrial quality control, significantly impacting neuroprotection in Parkinson's disease. Understanding its dual role in controlling mitophagy and maintaining bioenergetic homeostasis opens new possibilities for targeted drug development. Subsequent research should focus on structural and pharmacological modifications of HRI to enhance mitophagy while preventing mitochondrial depletion.
    Keywords:  DELE1; HRI (heme-regulated inhibitor kinase); ISR (integrated stress response); OMA1; PINK1; Parkin; Parkinson’s Disease (PD).; mitophagy
    DOI:  https://doi.org/10.2174/0118715273469080260515103009
  8. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00111-X. [Epub ahead of print]403 1-28
    Autophagy and primary cilium: A dynamic duo in cellular homeostasis and disease.
    Javiera Acevedo-Valdivieso, Camila Sandoval-Valenzuela, Daniela Pinto-Núñez, Isidora Reyes-Risso, Yorka Cheuquemilla, Diego Acuña-Catalán, Patricia V Burgos, Eugenia Morselli.
      The primary cilium (PC) is a microtubule-based organelle that functions as a signaling hub, coordinating critical cellular processes and maintaining cell homeostasis. Autophagy, a lysosome-mediated degradation pathway, has emerged as a key regulator of PC dynamics, which are crucial to control PC function. Ciliophagy, the selective autophagic degradation of damaged ciliary components, controls PC homeostasis ensuring PC integrity and function. This review highlights the intricate bidirectional crosstalk between the PC and autophagy, which influences cellular responses to environmental cues, nutrient availability, and hormonal signaling. Disruption of ciliophagy impairs PC-dependent signaling, contributing to the development of diseases such as ciliopathies and metabolic syndrome, among others. Furthermore, the overlap between ciliopathies and autophagy-related disorders underscores the crucial role of their interplay in health and disease. Recent evidence suggests that pharmacological modulation of autophagy could restore PC homeostasis, offering therapeutic potential for ciliopathies and other PC-associated diseases. Future research should focus on elucidating the molecular mechanisms driving ciliophagy in specific cell-types and exploring its therapeutic implications for clinical applications.
    Keywords:  Ciliopathies; Ciliophagy; Hypothalamic neurons; Kidney polycystic disease
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.005
  9. Mol Neurobiol. 2026 Jun 11. pii: 690. [Epub ahead of print]63(1):
    APOE4-Expressing Astrocytes Exhibit Parkinson's Disease-Related Pathology.
    Nechushtai Lior, Popov Anna, Haklai Roni, Michaelson M Daniel, Frenkel Dan, Pinkas-Kramarski Ronit.
      Parkinson's disease (PD) is characterized by motor symptoms that are mainly attributed to the progressive loss of dopaminergic neurons of the substantia nigra (SN). It is also characterized by abnormal inclusion vesicles, termed Lewy bodies (LBs), enriched with α-synuclein aggregates that may induce inflammation and neurotoxicity. The possibility that factors involved in other neurodegenerative diseases also affect PD-related pathologies, such as α-synuclein uptake, was examined. The apoe4 allele is a major genetic risk factor for Alzheimer's disease (AD) and has also been suggested to be involved in PD. Here, we examined the effects of APOE isoform expression on α-synuclein uptake and autophagy in astrocytes expressing the apoe3 or apoe4 alleles. Using multiple autophagy manipulations (EBSS, chloroquine, and rapamycin treatments), we found that α-synuclein uptake and autophagy readouts differ between APOE3 and APOE4 astrocytes, supporting a functional link between autophagy status and α-synuclein levels. Astrocytes expressing APOE4 exhibit reduced uptake of α-synuclein and reduced autophagy. Moreover, α-synuclein treatment inhibits autophagy mainly in APOE3-expressing cells. Additional experiments showed that the autophagy inhibitor chloroquine reduced α-synuclein uptake in APOE3 astrocytes but not in APOE4 astrocytes, while the autophagy enhancer rapamycin increased α-synuclein uptake in APOE4-expressing astrocytes. In addition, we found that Toll-like receptor 2 (TLR2) levels are elevated at both the mRNA and protein levels in APOE4-expressing astrocytes, whereas α-synuclein increased only TLR2 mRNA levels in APOE3-expressing astrocytes. Using the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), we found that it affects cell growth in both APOE3 and APOE4-expressing astrocytes. MPP+ treatment also reduced autophagy which was partially corrected by rapamycin. Taken together, these findings show that in astrocytes, APOE4 impairs α-synuclein uptake, which was emended by rapamycin and α-synuclein inhibits autophagy mainly in APOE3. These findings suggest that autophagy-targeting strategies can modulate astrocyte α-synuclein uptake; however, given the observed reductions in astrocyte cell number following rapamycin treatment, further optimization or examination of alternative autophagy modulators is needed.
    Keywords:  Alpha-synuclein; Apolipoprotein E4 (apoE4); Autophagy; Parkinson’s disease (PD)
    DOI:  https://doi.org/10.1007/s12035-026-05996-5
  10. Mol Biol Cell. 2026 Jun 11. mbcE25110536
    The ESCRT-0 protein HRS regulates hepatocellular lipid droplet catabolism.
    Mathilda M Willoughby, Ankit Shroff, Bridget E Crossman, Micah B Schott.
      Lipid droplets (LDs) are dynamic organelles that regulate lipid storage and metabolism pathways central to metabolic liver disease. LD turnover occurs in part through lysosomal catabolism (lipophagy), whereby LDs are delivered to lysosomes via two distinct trafficking pathways: autophagosome-dependent macrolipophagy and autophagosome-independent microlipophagy. However, the molecular machinery that regulates these two pathways, especially that of microlipophagy in mammalian cells, is poorly understood. In yeast, microlipophagy has been shown to rely on the endosomal sorting complex required for transport (ESCRT) protein family. Here, we used an ESCRT-specific RNAi library in hepatocytes, which identified the ESCRT-0 protein hepatocyte growth factor receptor substrate (HRS) as a critical regulator of LD homeostasis. HRS depletion leads to significant LD accumulation, driven by impaired LD catabolism rather than increased LD biogenesis. While HRS-deficient cells retain lipolytic activity, LD targeting via RAB5-mediated microlipophagy is reduced, and LD targeting by autophagosomes is increased. Consistent with these findings, HRS knockdown suppressed mTORC1 signaling, enhanced autophagosome formation, and reduced autophagic cargo degradation. Notably, despite unchanged lysosomal abundance, HRS knockdown elevated lysosomal pH, potentially impairing autophagic degradation and promoting LD accumulation. Overall, these findings identify HRS as a key regulator of LD turnover in mammalian cells, modulating lipophagy through lysosomal function.
    DOI:  https://doi.org/10.1091/mbc.E25-11-0536
  11. Curr Neuropharmacol. 2026 Jun 08.
    Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
    Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.
    Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.
    DOI:  https://doi.org/10.2174/011570159X473929260605103158
  12. bioRxiv. 2026 Jun 06. pii: 2026.06.04.730191. [Epub ahead of print]
    Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
    Thuraya M Mutawi, Shweta R Malvankar, Andrea Graziani, Udita Shah, Khanh Nguyen, David G Broadbent, Zachary Clark, Michaella J Rekowski, Susan M Lunte, Carlo Barnaba.
      Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD + /NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.
    DOI:  https://doi.org/10.64898/2026.06.04.730191
  13. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00615-7. [Epub ahead of print]45(6): 117537
    Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.
    Ruoxi Wang, Tina M Fortier, Xiaofeng Sun, Fei Chai, Panagiotis D Velentzas, Eric H Baehrecke.
      Selective removal of endoplasmic reticulum (ER) is important for cell health. Macroautophagy is the primary mechanism for the removal of the ER, but the ER can be cleared in a macroautophagy-independent manner. However, the physiological relevance and mechanisms underlying macroautophagy-independent ER clearance remain largely unknown. Here we show that ER is cleared by lysosomes in a macroautophagy Atg gene-independent manner during development. This developmentally programmed Atg-independent ER clearance by lysosomes requires the ER protein Vap33 that promotes ER and lysosome contact. Oxysterol-binding protein (Osbp) is known to associate with Vap33, and Osbp lysosomal localization is required for ER clearance in cells lacking macroautophagy. Significantly, the cholesterol transport-associated protein Start1 regulates ER and lysosome contact, macroautophagy-independent ER clearance, and cholesterol transport from ER to the lysosome. These studies reveal that Vap33, Osbp, and Start1 promote ER clearance by lysosomes that is associated with cholesterol trafficking.
    Keywords:  CP: cell biology; Drosophila; ER; ESCRT; Osbp; Start1; Vap33; lysosome
    DOI:  https://doi.org/10.1016/j.celrep.2026.117537
  14. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2531054123
    The autophagy protein ATG-9 promotes aversive learning in Caenorhabditis elegans through trafficking neuropeptide receptors.
    Wai Hou Tam, Yu-Cheng Tang, Hao-Han Shiu, Shang-Heng Tsai, Pei-Shu Jao, Chun-Liang Pan.
      Autophagy is a degradative process that maintains cellular homeostasis. Autophagy biogenesis occurs at synapses, but its impact on synaptic functions is incompletely understood. Here we show that, in Caenorhabditis elegans, synaptic ATG-9, the only transmembrane autophagy protein, contributes to aversive learning under mitochondrial stress. Analysis of the neuronal translatome reveals that autophagy is upregulated by stress in the octopaminergic RIC neuron and it promotes aversive learning. Inactivating autophagy genes, including atg-9, reduces aversive learning. Mitochondrial stress increases synaptic ATG-9 through AP-1- and AP-2-dependent exocytosis and endocytosis, respectively, and reducing synaptic ATG-9 impairs aversive learning. We further identify the FRPR-6 neuropeptide receptor as a substrate of ATG-9 modulation. Both atg-9 and frpr-6 promote aversive learning and RIC activities, and the abundance of FRPR-6 in the RIC neurite depends on atg-9. We postulate that ATG-9-containing synaptic compartments promote neuronal plasticity through modulating receptor trafficking to enable aversive learning under systemic mitochondrial stress.
    Keywords:  C. elegans; autophagy; memory; neuropeptides; synapse
    DOI:  https://doi.org/10.1073/pnas.2531054123
  15. Am J Pathol. 2026 Jun 11. pii: S0002-9440(26)00167-7. [Epub ahead of print]
    Metformin activates AMPK-TFEB signaling to restore lysosomal and mitochondrial homeostasis and suppress EMT in oxidative stress-injured retinal pigment epithelium.
    Sumin Son, Yoonha Kim, Kyoung-Jin Jang, Dong-Eun Kim.
      Disruption of lysosomal homeostasis and accumulation of dysfunctional mitochondria contribute to degenerative pathologies including age-related macular degeneration (AMD). Here, we investigated how inhibition of autophagic lysosome reformation (ALR) alters lysosomal dynamics, mitophagy, and downstream stress signaling in retinal pigment epithelial (RPE) cells, and whether these changes are pharmacologically reversible. In ARPE-19 cells, ALR inhibition by nocodazole or siRNA-mediated depletion of kinesin-1 (UKHC) and dynamin-2 (DNM2) induced enlarged lysosomes with reduced degradative capacity, impaired mitophagic turnover, and accumulation of dysfunctional mitochondria. ALR blockade increased reactive oxygen species (ROS) and cytosolic Ca2+, promoted activation and mitochondrial translocation of protein kinase C (PKC), and triggered phosphorylation of glycogen synthase kinase-3β with subsequent stabilization of SNAIL, consistent with epithelial-to-mesenchymal transition (EMT). Metformin restored lysosomal homeostasis by activating AMPK and enhancing transcription factor EB (TFEB)-dependent lysosome biogenesis, thereby improving autophagic flux, limiting ROS/Ca2+ accumulation, suppressing PKC activation, and attenuating EMT-associated marker changes. In a sodium iodate-induced oxidative injury model, metformin preserved RPE microtubule architecture and reduced lysosomal and mitochondrial abnormalities. Although these findings rely on a prolonged monolayer culture system and an acute injury model, they support a protective role for AMPK-TFEB-driven lysosome restoration in RPE stress resilience and suggest lysosome-directed repurposing potential for metformin in degenerative retinal disease.
    Keywords:  Autophagic lysosome reformation (ALR); Epithelial–mesenchymal transition (EMT); Lysosomal homeostasis; Mitochondrial dysfunction; Retinal pigment epithelium (RPE)
    DOI:  https://doi.org/10.1016/j.ajpath.2026.05.009
  16. Tissue Cell. 2026 Jun 10. pii: S0040-8166(26)00386-1. [Epub ahead of print]103 103692
    VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.
    Rabab S Hamad, Eman Hamza, Ebtehal M Abdel-Aal, Elsayed A Elmorsy, Hanan Eissa, Alshaimaa A Farrag, Ahmed Shata, Ghada M Nassar, Nesreen Elsayed Morsy, Ahmed A El-Mansy, Ahmed G Hamad, Eman R Abdellatif, Sameh Saber.
      Organelle contact sites are increasingly recognized as regulatory interfaces that coordinate lipid transfer, ion signaling, and metabolic adaptation. In neurons, communication among the endoplasmic reticulum (ER), lysosomes, and mitochondria is essential for cellular homeostasis. Recent studies have identified vacuolar protein sorting 13 homolog C (VPS13C), a lipid transport protein, as a key mediator of ER-lysosome tethering and as an important component of the response to lysosomal stress. Structural analyses show that VPS13 family proteins form elongated lipid transport channels that are proposed to facilitate phospholipid transfer between adjacent membranes. Following lysosomal damage, VPS13C is recruited to ER-lysosome contact interfaces, where it forms tethering bridges that may support membrane repair by enabling high-capacity lipid transfer from the ER to lysosomal membranes. Beyond membrane repair, these contact interfaces may also participate in broader organelle communication networks. ER-lysosome contacts can occur in proximity to ER-mitochondria junctions, potentially forming multi organelle signaling hubs that coordinate lipid redistribution, calcium signaling, and mitochondrial adaptation. These signals may influence downstream responses, including activation of TFEB and TFE3, which regulate lysosomal biogenesis and autophagy. Disruption of this contact site network has emerged as a potential contributor to Parkinson's disease. Loss of VPS13C function is associated with altered lysosomal homeostasis and intersects with pathogenic pathways involving α-synuclein aggregation, PINK1/Parkin-mediated mitophagy, and LRRK2 signaling. This review presents a framework in which ER-lysosome tethering is considered part of a staged cellular damage response linking membrane repair, metabolic coordination, and transcriptional adaptation.
    Keywords:  ER-lysosome tethering; Lipid transfer; Lysosomal membrane repair; Organelle contact sites; Parkinson’s disease; VPS13C
    DOI:  https://doi.org/10.1016/j.tice.2026.103692
  17. Biofactors. 2026 May-Jun;52(3):52(3): e70124
    Lipid Codes and Lipid-Binding Proteins as Central Regulators of Autophagy.
    Abhishek Kumar, Debasish Kumar Ghosh.
      Autophagy is increasingly understood as a lipid-governed membrane program rather than a solely protein-driven degradative pathway. This review combines molecular and mechanistic evidence showing how lipid molecules, metabolic enzymes, and membrane physical properties coordinate autophagy from induction to lysosomal degradation. We highlight phosphoinositide microdomains and their cognate kinases and phosphatases as spatial cues that nucleate phagophores, control maturation, and regulate lysosome reformation. We also discuss alternative phosphoinositide sources, sphingolipid and ceramide signaling, phosphatidic acid and diacylglycerol metabolism, fatty-acyl composition, and acyl-CoA signaling as determinants of membrane curvature, tension, leaflet asymmetry, and phase behavior in autophagy. Key protein effectors and their lipid binding motifs and domains are integrated into a model in which lipid chemistry and mechanics gate enzymatic activities. We present integrated lipid-protein-biophysics approaches to highlight outstanding questions and uncover predictive principles.
    Keywords:  autophagosome biogenesis; lipid regulation of autophagy; lipid‐protein interactions; membrane biophysics and curvature; phosphoinositide signaling
    DOI:  https://doi.org/10.1002/biof.70124
  18. Mol Neurobiol. 2026 Jun 11. pii: 687. [Epub ahead of print]63(1):
    The Role of PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury: A Review of Recent Advances.
    Liping Xing, Annan Liu, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.
      Mitophagy, the selective clearance of damaged mitochondria, is a critical mechanism for mitochondrial quality control in cerebral ischemia-reperfusion injury (CIRI). The PINK1/Parkin signaling pathway is the primary ubiquitin-dependent pathway mediating mitochondrial autophagy, and its functional status directly influences the pathological progression of CIRI. This review systematically examines the molecular activation mechanisms of PINK1/Parkin-mediated mitophagy in CIRI and analyzes its interactions with core pathological processes, including oxidative stress, calcium homeostasis disruption, ferroptosis, and neuroinflammation. Furthermore, we summarize the latest advances over the past 5 years in modern medical strategies, traditional Chinese medicine interventions, and gene and protein-targeted therapies directed at this pathway. By integrating existing evidence, this review is aimed at deepening our understanding of the molecular mechanisms underlying CIRI and providing a theoretical foundation for developing novel neuroprotective therapies that target this pathway.
    Keywords:  Cerebral ischemia-reperfusion injury; Mitophagy; PINK1/Parkin signaling pathway; Pathological mechanisms; Potential interventions
    DOI:  https://doi.org/10.1007/s12035-026-05997-4
  19. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2528668123
    Disruption to TFEB signaling and autophagy in newly formed oligodendrocytes leads to aberrant generation of CNS myelin.
    Daniela Barbosa, Aksheev Bhambri, Miguel Vasquez, Yihe Zhang, Gabrielle Sanchez, Katherine J Wert, Natalia V Gounko, Mark H Ellisman, Lu O Sun.
      Myelin is a defining feature of the vertebrate nervous system, yet the cellular and molecular mechanisms governing its integrity remain poorly understood. Here, using volume electron microscopy and a knock-in mouse line targeting newly formed oligodendrocytes, we reconstruct early optic nerve myelination and examine retinal ganglion cell axon ensheathment. We observe that newly formed myelin sheaths exhibit membrane protrusions and occasional degenerative myelin "whorls." Conditional disruption of the transcription factor EB (TFEB)-autophagy pathway in newly formed oligodendrocytes significantly increases the abundance of these aberrant myelin structures, indicating that this pathway is required for proper myelin formation and integrity. Importantly, this pathway acts independently of the well-established function of TFEB that represses myelin sheath growth. Together, our findings identify a role for TFEB-dependent autophagy in establishing proper myelin structure during development, providing insights into the oligodendrocyte-intrinsic mechanisms that regulate myelin integrity.
    Keywords:  axon ensheathment; myelin integrity; newly formed oligodendrocytes; volume electron microscopy
    DOI:  https://doi.org/10.1073/pnas.2528668123
  20. J Biol Chem. 2026 Jun 12. pii: S0021-9258(26)02117-4. [Epub ahead of print] 113245
    Atg23 interacts with both the N- and C-termini of Atg9 via a hydrophobic binding pocket.
    Zhanibek Bekkhozhin, Kelsie A Leary, Michael J Ragusa.
      Macroautophagy is a cellular process where cytosolic material is captured in double membrane vesicles, termed autophagosomes, which fuse with the vacuole or lysosomes leading to the degradation of the captured contents. The biogenesis of autophagosomes is initiated by the fusion of a few small vesicles which contain the integral membrane protein Atg9. Atg9 vesicle trafficking is, in part, regulated by the peripheral membrane protein Atg23. However, the structure of Atg23 and the mechanism by which Atg23 interacts with Atg9 are currently unknown. Therefore, we determined the crystal structure for a monomeric form of Atg23 and characterized the interaction between Atg23 and Atg9. This work reveals that Atg23 contains a novel fold which is consistent with the AlphaFold 3 prediction except that the helices running towards the dimerization region have a bend giving a more curved global architecture than the prediction. In addition, we demonstrate that conserved sequences at the very distal regions of the N and C-terminal disordered regions of Atg9 bind to a hydrophobic cavity on Atg23. These Atg23 binding regions are distinct from the previously identified Atg11 binding region within the disordered N-terminus of Atg9, suggesting that Atg9 contains multiple different protein interaction regions within its disordered termini.
    Keywords:  X-ray crystallography; autophagy; membrane trafficking; phospholipid vesicle; protein-protein interaction
    DOI:  https://doi.org/10.1016/j.jbc.2026.113245
  21. Autophagy. 2026 Jun 13.
    E-cigarette aerosols induce the hydrolysis of lysosomal glycerophospholipids through PLA2G4A activation initiated by nicotine binding to CHRNA3/α3 nAchr in airway epithelial cells.
    Yongquan Yu, Shuyu Xu, Liu Yang, Shuge Shu, Haojie Zhou, Zhencheng Hua, Li Wang, Yingran Zhu, Aiming Shi, Rong Xia, Chao Chen, Shou-Lin Wang.
      Accumulating evidence has demonstrated a significant association between e-cigarette exposure and airway epithelial damage. Nevertheless, the molecular drivers orchestrating this pathology remain unclear. Here, we demonstrated that nicotine is the key component of e-cigarette aerosols that induced pathogenic changes, including apoptosis, oxidative stress, and mucus overproduction, in mouse airway epithelium and in human bronchial epithelial (HBE) cells. We further established that the nicotine of e-cigarette aerosols induced autophagosome formation via MTOR inhibition, while concurrently suppressing autolysosomal degradation through lysosomal membrane permeabilization (LMP). Restoration of lysosomal membrane integrity reversed e-cigarette aerosol-induced LMP and the subsequent macroautophagy/autophagy inhibition, thereby alleviating airway epithelial damage. Mechanistically, nicotine of e-cigarette aerosols permeabilized lysosomal membranes via calcium-dependent activation of PLA2G4A, which hydrolyzed the sn-2 ester bond of lysosomal glycerophospholipids, generating lysophospholipids. This process was initiated by nicotine binding to CHRNA3/α3 nAChR, a ligand-gated ion channel whose activation triggered intracellular Ca2+ overload. Genetic or pharmaceutical inhibition of CHRNA3 reduced intracellular Ca2+ content, abolishing PLA2G4A activation. This inhibited lysosomal glycerophospholipid hydrolysis, thereby attenuating LMP and subsequently resolving autophagic flux blockade and cytotoxicity in HBE cells. Moreover, the role of CHRNA3-mediated PLA2G4A activation in e-cigarette aerosol-induced autophagy-lysosome dysfunction and cellular toxicity was validated in human lung organoids. Overall, our study underscores the importance of CHRNA3 activation, as a molecular initiating event (MIE), in the regulation of PLA2G4A-mediated hydrolysis of glycerophospholipids and autophagic flux impairment, and CHRNA3 inhibition could serve as a potential therapy for airway disorders induced by e-cigarette aerosols.
    Keywords:  Airway epithelial damage; autophagy; cytosolic phospholipase A2; electronic cigarette aerosol; lysosomal membrane permeabilization; nicotine; nicotinic acetylcholine receptor
    DOI:  https://doi.org/10.1080/15548627.2026.2689038
  22. Free Radic Biol Med. 2026 Jun 08. pii: S0891-5849(26)00821-X. [Epub ahead of print]254 1-17
    Restoring BECN1-mediated autophagy mitigates acute lung injury caused by zinc oxide nanoparticles.
    Lejiao Mao, Meiling Tan, Xuejun Jiang, Jun Zhang, Ge Xu, Yujia Zhang, Shanshan Zhang, Caixia Gao, Xia Qin, Chengzhi Chen, Zhen Zou.
      Pulmonary inhalation of zinc oxide nanoparticles (ZnONPs) triggers metal fume fever in humans and acute lung injury (ALI) in animal experiments. Previous evidence suggests that autophagy is involved in the pathogenesis of ZnONPs-induced ALI, with BECN1/Beclin1-dependent autophagy and mitophagy playing a central role. In the present study, heterozygous-deficient (Becn1+/-) mice exhibit significantly exacerbated ALI compared to Becn1+/+ controls following ZnONPs exposure. Immunoprecipitation-mass spectrometry analysis revealed that ZnONPs remodel the BECN1 protein interactome, enriching pathways related to autophagy, mitophagy, and mitochondrial quality control. Furthermore, Becn1 haploinsufficiency disrupted autophagic progression, causing accumulation of dysfunctional mitochondria within mitophagosomes. Notably, administration of Tat-Beclin1, a cell-permeable autophagy-inducing peptide, effectively ameliorated ZnONPs-induced ALI in both Becn1+/+ and Becn1+/- mice exposed to ZnONPs. Crucially, macrophage-specific Becn1 knockout mice recapitulated the exacerbated injury phenotype, identifying myeloid BECN1 as the critical cellular protector. Mechanistically, Tat-Beclin1 restored autophagic progression and facilitated mitochondrial degradation, thereby attenuating ROS production and inflammatory cascades. These findings demonstrate that pharmacological restoration of BECN1 via Tat-Beclin1 offers a viable strategy for treating nanoparticle-induced metal fume fever and ALI.
    Keywords:  Acute lung injury; Autophagy; BECN1; Tat-Beclin1 peptide; Zinc oxide nanoparticles
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.317
  23. Autophagy. 2026 Jun 13.
    MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
    Ming-Hua Wu, Xue-Ming Zhu, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.
      Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in Magnaporthe oryzae remains poorly understood. In our recent study, we found that upon outer mitochondrial membrane disruption, inner mitochondrial membrane (IMM) protein MoCox6 is rendered available for engagement with cytosolic MoAtg5 and MoAtg14 to drive mitophagy, whereas MoSirt5-mediated desuccinylation of MoCox6 at K144 weakens these interactions and thereby restrains mitophagic flux. Further analyses identified Asp95 at the MoSirt5-MoCox6 interface as a pivotal residue coupling mitochondrial metabolic control to mitophagy. A high-throughput virtual screening targeting an Asp95-centered pocket in MoCox6 identified Pan-RAS-IN-1, a small molecule that effectively suppresses rice blast incidence and exhibits broad-spectrum antifungal activity. Collectively, these findings identify MoCox6 as an IMM regulator of mitophagy whose succinylation state links mitochondrial metabolic cues to mitochondrial turnover, while highlighting mitochondrial quality control as a potential target for fungal disease management.
    Keywords:  Fungicide target; MoCox6; magnaporthe oryzae; mitophagy; succinylation
    DOI:  https://doi.org/10.1080/15548627.2026.2689458
  24. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00113-3. [Epub ahead of print]403 29-63
    Unraveling the interplay of glycolysis, lactylation, and autophagy.
    Marco Cordani, Federica Michetti, Raffaele Strippoli, Cristiano Rumio, Guillermo Velasco, Fabrizio Marcucci.
      Glycolysis and macroautophagy (hereafter autophagy) are fundamental biological processes involved in many physiological and pathological settings. Both have been shown to play pivotal roles in tumor initiation and progression. Metabolic reprogramming has been proposed as one of the hallmarks of cancer although in recent times the role of oxidative metabolism in tumorigenesis has been reevaluated and it seems more appropriate to talk about upregulated glycolytic or oxidative metabolism. Autophagy on the other hand, has been shown to play an antitumor role in initial stages of tumorigenesis, while having a tumor-promoting role in tumor progression. Glycolysis and autophagy have long been known to have a complex relationship with each other. In this article we give a picture of this relationship. We show that glycolysis can promote either upregulation or inhibition of autophagy. Vice versa, autophagy can also either promote upregulation or inhibition of glycolytic metabolism. These are highly contradictory effects that appear difficult to reconcile. We suggest that induction of glycolysis or autophagy in the presence of nutrient deprivation or nutrient sufficiency may be at the origin of at least part of these contradictory findings.
    Keywords:  Autophagy; Glycolysis; Lactylation; Metabolic reprogramming; Post-translational modifications
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.007
  25. Nat Commun. 2026 Jun 10.
    SEC14L2 couples chaperone-mediated autophagy to microtubule stability by targeting Stathmin 1.
    Guangyuan Li, Hanfang Xu, Bo Gong, Shunji Jia.
      Microtubule dynamic instability underpins cellular architecture, division, and intracellular trafficking, yet how selective proteolytic pathways tune core microtubule regulators remains incompletely understood. Here, we identify SEC14L2 (SEC14-like lipid binding 2), a multidomain lipid transfer protein, as a determinant of microtubule organization and cellular architecture by limiting the accumulation of the microtubule-destabilizing factor Stathmin 1 (STMN1). We further show that STMN1 is a substrate of chaperone-mediated autophagy (CMA) and that SEC14L2 is required for efficient CMA-dependent STMN1 turnover. SEC14L2 loss is associated with reduced CMA activity, STMN1 stabilization, collapse of the microtubule network, and perinuclear organelle clustering. In breast cancer cell models, perturbation of this SEC14L2-CMA-STMN1 axis alters responses to microtubule-targeting agents.
    DOI:  https://doi.org/10.1038/s41467-026-74325-0
  26. PLoS Pathog. 2026 Jun;22(6): e1012998
    The Legionella pneumophila type IVb secretion system effector BinA subverts amino acid transport to sensitize TORC1 signaling in macrophages.
    Magdalena Circu, Reneau Castore, Brian Latimer, Stephanie Shames, Craig R Roy, Ana-Maria Dragoi, Stanimir S Ivanov.
      Legionella pneumophila is an environmental Gram-negative bacterium that parasitizes unicellular protozoa and can cause severe pulmonary infections when aerosolized bacteria are inhaled by humans. One critical aspect of Legionella pathogenesis is the establishment in the cytosol of infected macrophages of a unique ER-derived vacuole, that requires a sustained supply of host lipids during expansion. Subversion of pro-lipogenic pathways downstream of the metabolic checkpoint kinase mTOR (Mechanistic Target of Rapamycin) are critical for niche expansion. In eukaryotic cells, amino acids sufficiency and growth factor sensory signals converge on mTOR to ensure metabolic processes are coupled to nutrients/energy availability. Legionella can trigger mTOR signaling in infected cells by increasing the intracellular abundance of amino acids through inhibition of host translation. Here, we describe a novel mechanism by which Legionella sensitizes mTOR in infected macrophages. A forward genetic screen identified Lpg0393 protein as a putative bacterial mTOR regulator that contains a VPS9-domain typically found in eukaryotic GEFs (Guanine nucleotide exchange factors) for Rab5 GTPase family members (Rab5/Rab21/Rab22). We uncovered that Lpg0393 lowers the activation threshold for mTOR signaling upon stimulation with arginine or leucine by promoting anterograde trafficking of amino acid permeases through subversion of the small GTPases Rab21 and Rab22. Data from cells expressing either a bacterial or a eukaryotic mTOR sensitizing factor uncovered two distinct non-cytosolic Arg/Leu pools that fuel mTOR activation in parallel - one regulated by Rab21/22 and the other by Rab5. Consistent with the role of mTOR in expansion of the Legionella-occupied organelle, deletion of Lpg0393 also resulted in premature vacuolar rupture in a mTOR-dependent manner. All together, we have identified a novel bacterial mTOR regulator and consistent with its reported functions we propose Lpg0393 is named as BinA (Bacterial initiator of TORC1 signaling and an activator of Rab5 family GTPases).
    DOI:  https://doi.org/10.1371/journal.ppat.1012998
  27. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2520331123
    Dysregulation of autophagosome-mitochondria contacts contributes to autophagy dysfunction and neurodegeneration in tauopathy.
    Nuo Jia, Hongyuan Guan, Yantao Zuo, Yu Young Jeong, Niharika Amireddy, Gavesh Rajapaksha, Cuauhtemoc Ulises Gonzalez, Nora Jaber, Yun-Kyung Lee, Marialaina Nissenbaum, David J Margolis, Wei Dai, Alexander W Kusnecov, Qian Cai.
      Mitochondria (Mito) engage in extensive communication with other organelles through membrane contacts. Perturbed mitochondria-organelle interactions are indicated in a variety of neurodegenerative diseases, but the underlying mechanisms remain poorly understood. Here, we report a class of mitochondria-organelle communication: autophagosome/autophagic vacuole (AV)-Mito contact, which exhibits hypertethering in tauopathy neurons, consequently hampering AV retrograde transport. Such defects are attributed to accelerated turnover of the contact release factor TBC1D15, triggered by mitochondrial bioenergetic deficit-induced hyperactivity of the adenosine monophosphate-activated protein kinase (AMPK). Increasing TBC1D15 levels or repressing AMPK activity normalizes AV-Mito contact release and restores retrograde transport of AVs, thereby increasing autophagic cargo clearance and reducing tau burden in tauopathy axons. Furthermore, overexpression of TBC1D15 enhances autophagic clearance and attenuates tau pathology, alleviating neurodegeneration and cognitive dysfunction in tauopathy mice. Taken together, our study provides mechanistic insights into AV-Mito contact dysregulation in tauopathy-related autophagy failure, laying the groundwork for the development of potential therapeutics to combat tauopathy diseases.
    Keywords:  autophagosome retrograde transport; autophagosome–mitochondria contact; autophagy; mitochondrial bioenergetics; tauopathy
    DOI:  https://doi.org/10.1073/pnas.2520331123
  28. Int J Mol Sci. 2026 Jun 03. pii: 5070. [Epub ahead of print]27(11):
    Contradictory Effects on Hepatocytes in ASMD.
    Maksim Sysoev, Dmitri Solovyov, Aleksandr Shestopalov, Sergey Kutsev.
      Acid sphingomyelinase deficiency is a lysosomal storage disease that is characterized by the systemic accumulation of sphingomyelin in cells. This condition is frequently associated with hepatomegaly and hepatic dysfunction, with 91.4% of patients showing clinically relevant signs of liver involvement. Both clinical observations and experimental models show excessive sphingomyelin accumulation in hepatocytes. Studies using ASMD models have yielded conflicting results, showing hepatoprotective effects on one hand and detrimental effects on the other. Murine models demonstrated hepatoprotective effects of ASMD due to the modulation of endoplasmic reticulum stress. Patients with ASMD exhibit signs of impaired autophagy, which can lead to the accumulation of damaged cellular components and metabolic dysfunction. Furthermore, patients exhibit disrupted lipid metabolism, highlighting the dysfunction of hepatic lipid homeostasis. This review explores the involvement of ASMD in hepatocytes to better understand the disease mechanisms and possible therapeutic approaches.
    Keywords:  acid sphingomyelinase; acid sphingomyelinase deficiency; autophagy; hepatocytes; liver dysfunction; lysosomal storage disease; lysosomes; sphingomyelin
    DOI:  https://doi.org/10.3390/ijms27115070
  29. Autophagy. 2026 Jun 08.
    PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.
    Xiaoyi Sun, Jiazhen Dong, Xiaowei Liang, Jiangwei Peng, Yuncai Chen, Rui Yin, Tao Tan, Lei Bai, Ke Lan.
      Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several malignancies, including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease, harbors a DNA replication helicase encoded by ORF44 that is crucial for viral replication and pathogenesis. In this study, we identified the host PFN1 (profilin 1), a well-known actin-binding factor, as an inhibitor of KSHV lytic replication functioning via the macroautophagy/autophagy-lysosomal degradation pathway targeting ORF44. Mechanistic analyses revealed that PFN1 interacts with ORF44, leading to enhanced polyubiquitination of PFN1. Notably, the E3 ubiquitin ligase TRIM37 (tripartite motif containing 37) facilitates the polyubiquitination of lysine residues at position 116 of PFN1, which serves as a critical recognition motif for the cargo receptor SQSTM1/p62 (sequestosome 1), which is pivotal for the subsequent autophagic degradation of ORF44. Overall, our findings revealed a previously uncharacterized antiviral function of PFN1, highlighting its potential as a novel therapeutic avenue for the treatment of KSHV-associated malignancies.
    Keywords:  ORF44; PFN1; SQSTM1/p62; TRIM37; ubiquitination; viral protein degradation; viral replication
    DOI:  https://doi.org/10.1080/15548627.2026.2686417
  30. Nat Protoc. 2026 Jun 10.
    Robust analytical methods for bis(monoacylglycero)phosphate profiling in health and disease.
    Wentao Dong, Kwamina Nyame, Eshaan S Rawat, Uche N Medoh, Jian Xiong, Caio C Bonin, Hisham N Alsohybe, Hunter Y Liu, Sara Gomes, Tammy Shalit, Marianna Arnold, Frank Hsieh, Esther Sammler, Monther Abu-Remaileh.
      Bis(monoacylglycero)phosphates (BMPs), a distinct class of anionic phospholipids predominantly found in late endosomes and lysosomes, plays a pivotal role in supporting lysosomal functions and maintaining metabolic homeostasis. Dysregulation of BMPs is associated with an array of disorders, notably neurodegenerative diseases. However, the identification and quantitation of BMP remains difficult because of its structural similarity to its isomer, phosphatidylglycerol (PG), thus necessitating robust analytical methods for accurate and reliable BMP profiling. In this study, we present comprehensive liquid chromatography (LC)-tandem mass spectrometry (MS2) methodologies for the precise and systematic analysis of BMP species in biological samples. We detail LC/MS methods for both an untargeted Orbitrap mass spectrometer and a targeted triple quadrupole mass spectrometer. We use differences in hydrophobicity and structure to annotate BMPs and PGs on the basis of retention time and positive-mode MS2 fragmentation patterns, respectively. Because genetic ablation of the BMP synthase CLN5 leads to specific depletion of BMPs but not PGs, lipid extracts from CLN5 knockout and wild-type cells can be compared to confidently annotate BMPs when MS2 data are incomplete. Lipid extraction and preparation of samples for LC/MS takes ~4 h, unattended LC/MS instrument time depends on the number of samples and computer-based data analysis takes ~1 d. Altogether, this approach constitutes a robust method for BMP profiling and annotation, furthering research into health and disease.
    DOI:  https://doi.org/10.1038/s41596-026-01379-1
  31. Virology. 2026 Jun 05. pii: S0042-6822(26)00216-3. [Epub ahead of print]623 111001
    Autophagy in VZV infection: To degrade, or to deliver?
    Zujie Shen, Ningshao Xia, Tong Cheng, Wei Wang.
      Varicella-zoster virus (VZV) interacts with autophagy in a manner distinct from that of many other herpesviruses. Rather than broadly blocking autophagic flux, VZV generally induces a functional autophagic response and appears to use this pathway to support productive infection. Available data suggest that autophagy mainly plays a pro-viral role during the VZV lytic cycle in epithelial cells and fibroblasts by promoting viral glycoprotein maturation, secondary envelopment, intracellular trafficking, and egress. However, emerging evidence indicates that autophagy can exert antiviral and protective effects in neuronal cells and hematopoietic cells, highlighting the cell-type-dependent duality of autophagy in VZV infection. A notable feature of this process is the convergence of autophagic and endosomal pathways, through which VZV redirects autophagy-related vesicle trafficking away from lysosomal degradation and toward transport and exocytosis. Mechanistically, ER stress-UPR signaling acts as a major upstream regulator of VZV-induced autophagy, while the contributions of mTOR, ESCRT, and TLR-related pathways remain to be fully elucidated. This review summarizes recent advances in the mechanisms, functions, and cell-context dependence of VZV-autophagy interactions and highlights key unresolved questions relevant to viral pathogenesis and host-directed antiviral strategies.
    Keywords:  Autophagic flux; Autophagy; Endoplasmic reticulum stress; Unfolded protein response; Varicella-zoster virus; Viral egress
    DOI:  https://doi.org/10.1016/j.virol.2026.111001
  32. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  33. JHEP Rep. 2026 Jun 06. pii: S2589-5559(26)00188-6. [Epub ahead of print] 101917
    The purinergic receptor P2X4R stimulates macro-autophagy with impact on lipid droplet size in fatty liver.
    Pebrier Thibault, Garcin Isabelle, Fayol Olivier, Muthukulavan Marzaan, Doignon Isabelle, Bouzhir Latifa, Gautherot Julien, Cauchois Florent, Dellis Olivier, Le Guilcher Camille, Guettier Catherine, Merlen Gregory, Tordjmann Thierry.
       BACKGROUND/AIMS: P2X4R is a lysosomal ATP-gated cation channel receptor, playing roles in liver pathophysiology through poorly understood mechanisms. This study aimed to define the role of P2X4R in macroautophagy and lipid droplet (LD) homeostasis.
    METHODS: We used P2X4R-KO, LC3-GFP transgenic and WT mice, a specific P2X4R antagonist (BAY1797), and three experimental models of steatosis (n=5-10 mice/group). Autophagy flux was measured in human embryonic kidney (HEK) reporter cell line, and Atg5-/- mouse embryonic fibroblast (MEF) cells. Oleic acid (OA) cell loading, LC3-II western blots, Oil Red O and LipidTox cell and tissue staining were also performed.
    RESULTS: The autophagic flux in the liver and in primary isolated hepatocytes was decreased in P2X4R-KO as compared with WT mice, as well as in BAY1797 (as compared with vehicle)-treated WT animals and hepatocytes. P2X4R overexpression stimulated the autophagic flux, pointing to an impact of P2X4R on lysosome-autophagosome fusion. BAY1797 treatment in fasted mice as well as in both MCD and HFHSC diet models resulted in small LD, instead of large LD steatosis (vehicle-treated mice) and stimulated cytosolic lipolysis. Similar results were observed in vitro in OA-loaded primary hepatocytes, as well as in MEF in which BAY1797 inhibited lipophagy and stimulated cytosolic lipolysis, resulting in smaller size LDs. Lysosome position analysis upon starvation revealed that P2X4R inhibition interfered with lysosomal trafficking in vitro. In MASLD patients (n=24) a correlation was found between LD size, autophagic flux and P2X4R expression.
    CONCLUSION: P2X4R inhibition reduced the autophagic flux in hepatocytes, resulting in LD size reduction, during fasting- as well as diet-induced steatosis in mice. P2X4R is proposed as a new therapeutic target to modulate lipophagy in the liver.
    IMPACT AND IMPLICATIONS: Our study provides in vitro and in vivo evidence that P2X4R is a regulator of macro-autophagy, and thereby impacts on lipid droplet homeostasis in the liver. Both genetic deletion and pharmacologic specific inhibition of P2X4R results in lipid droplet size reduction in three murine models of fatty liver, in association with inhibition of lipophagy, stimulation of lipolysis and reduction of liver inflammation. Finally in humans, we found in a series of MASLD patients that P2X4R expression was correlated with autophagy flux and lipid droplet size. Altohether, our data support strongly the idea that P2X4R inhibition is hepato-protective in the context of MASLD.
    Keywords:  autophagy; lipid droplets; lipophagy; purinergic receptor P2X4R; steatosis
    DOI:  https://doi.org/10.1016/j.jhepr.2026.101917
  34. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00121-2. [Epub ahead of print]403 145-176
    Role of autophagy in adipose tissue: Implications for metabolic health.
    Núria Borràs-Ferré, Antonio Zorzano, Montserrat Romero.
      Autophagy is increasingly considered a key regulator of adipose tissue biology, with growing evidence linking this cellular degradation pathway to crucial aspects of metabolic health. In recent years, research has revealed that autophagy influences adipocyte differentiation, lipid handling, mitochondrial quality control, and inflammatory responses within adipose depots. These functions are essential for maintaining the plasticity and functionality of both white and brown adipose depots. As our understanding of how autophagy shapes fat tissue dynamics grows, this process is emerging as a promising target for treating obesity and related metabolic disorders. Future clinical applications may involve precision therapeutics that combine pharmacological, dietary, and genetic tools to modulate autophagy in an adipose tissue-specific and personalized manner. In this review, we summarize current knowledge of the role of autophagy in adipose tissue physiology and its impact on systemic metabolism. We also discuss how autophagy dysregulation contributes to metabolic diseases such as obesity and insulin resistance, and therefore its potential use as a therapeutic target in clinical practice.
    Keywords:  Adipose tissue; Autophagy; Endosomes; Metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.015
  35. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00112-1. [Epub ahead of print]403 65-83
    Autophagy and type 2 diabetes: Bridging the gap in metabolic health.
    Agustina Creus, Leonardo Ortega, David Sebastián.
      Autophagy is a catabolic process key in the maintenance of cellular homeostasis in response to intracellular stress, and able to sense and transmit metabolic changes within tissues. Therefore, autophagy has emerged as a key process for metabolic homeostasis at whole body level. In this regard, alterations in autophagy are associated with the development of metabolic diseases, such as type 2 diabetes (T2D). Impairment in autophagy in metabolically relevant tissues including liver, muscle, adipose tissue and pancreatic β-cells, results in a further aggravation of diabetes-related metabolic alterations. This Review offers a comprehensive overview of our current understanding of autophagy and its role in the pathophysiology of T2D. Importantly, due to the relevance of autophagy in the development of T2D, we also summarize recent advancements in interventions and therapies targeting autophagy, providing insights into its therapeutic potential to combat this disease.
    Keywords:  Adipose Tissue; Autophagy; Diabetes; Liver; Metabolic Disease; Muscle; β-cell
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.006
  36. bioRxiv. 2026 Jun 02. pii: 2026.06.01.729255. [Epub ahead of print]
    HKDC1 contributes to aberrant lysosome-mitochondria contact in Niemann-Pick disease type C.
    Raffaele Pastore, Jack Stanley, Szilvia Kiraly, Christelle Dubois, Jlenia Monfregola, Antonio De Luca, Germano Guerra, Mark Skehel, Andrea Ballabio, Frances M Platt, Emily R Eden.
      Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder comprising two clinically indistinguishable but genetically distinct subtypes caused by mutations in NPC1 , or NPC2 . The specific impact of each deficiency on cellular homeostasis remains poorly defined due to the phenotypic heterogeneity of patient-derived models and a lack of isogenic platforms for comparative study. Here we established isogenic ARPE19 models of NPC1 and NPC2 deficiency that faithfully recapitulate hallmark pathologies, including homogeneous lysosomal expansion and lipid sequestration. Direct comparison of these isogenic lines revealed a fundamental divergence in organelle crosstalk: while both genotypes exhibit comparable lipid accumulation, expanded mitochondria-lysosome contact sites (MLCs) are observed exclusively in NPC1 -/- cells. Using StARD3-targeted proximity labelling and quantitative proteomics, we identified the mitochondrial protein HKDC1 as an MLC regulator. We demonstrate that HKDC1 is markedly upregulated in NPC1 -/- cells and that its overexpression drives MLC expansion in wild-type cells. Thus our study uncovers a homeostatic role for HKDC1-mediated organelle remodelling and demonstrates the power of isogenic modelling for identifying novel regulators of organelle architecture and potential therapeutic targets.
    DOI:  https://doi.org/10.64898/2026.06.01.729255
  37. Food Sci Nutr. 2026 May;14(5): e71916
    Targeting the RNF31-TFEB-NLRP3 Axis With a Curcumin Analog to Restore Autophagy and Alleviate Intestinal Inflammation.
    Lu Han, Yang Xie, Chunyan Zeng, Youxiang Chen.
      Inflammatory bowel disease (IBD) is characterized by impaired autophagy and chronic inflammation. Although the E3 ubiquitin ligase RNF31 is upregulated in IBD, its pathogenic mechanisms remain incompletely understood. To address this, a combination of in vitro and in vivo methods was employed. In vitro, lipopolysaccharide (LPS)-stimulated cell models were used to analyze transcription factor EB (TFEB) phosphorylation, its interaction with RNF31, ubiquitination, and subcellular localization. In vivo, a DSS-induced IBD mouse model was used to assess intestinal pathology, inflammation, and RNF31-TFEB-NLRP3 axis proteins after treatment with a novel synthetic curcumin analog (CM-C1). We identified TFEB as a novel substrate of RNF31. LPS-induced phosphorylation of TFEB promoted its binding to RNF31 (via TFEB-S281/T276 and RNF31-K908), leading to TFEB ubiquitination, proteasomal degradation, suppressed autophagy, and subsequent NLRP3 inflammasome activation. The bioavailable TFEB activator CM-C1 directly disrupted the RNF31-TFEB interaction. This action promoted TFEB nuclear translocation, restored autophagic flux, alleviated intestinal inflammation in vitro and in vivo, and beneficially remodeled the gut microbiota. Our study unveils the RNF31-TFEB-NLRP3 axis as a pivotal pathogenic pathway in IBD and nominates CM-C1, which targets this axis, as a promising multimodal therapeutic candidate.
    Keywords:  CM‐C1; RNF31; TFEB; autophagy dysfunction; inflammatory bowel disease
    DOI:  https://doi.org/10.1002/fsn3.71916
  38. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00114-5. [Epub ahead of print]403 85-121
    Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.
    Riccardo Ballarò, Fabio Penna, Marc Beltrà.
      Cancer cachexia is a multifactorial syndrome characterized by body weight loss, muscle wasting, and systemic metabolic alterations, significantly contributing to patient morbidity and mortality. A key feature of cachexia is the excessive degradation of muscle proteins and mitochondria, largely mediated by autophagy. Although hyperactivation of autophagy has been widely recognized as a hallmark of cancer cachexia, its precise role in exacerbating muscle atrophy through enhanced proteolysis and mitochondrial disposal remains a subject of ongoing debate. This review provides a comprehensive overview of previous milestones and recent advancements in understanding autophagy's role in cancer cachexia, with particular focus on its impact on skeletal muscle and liver, as well as its contribution to tumor metabolic flexibility. Additionally, the review explores emerging therapeutic strategies aimed at modulating autophagy, including exercise, exercise mimetics, and novel molecules to selectively target specific branches of autophagy. By synthesizing current evidence, this review highlights the need for further research into the mechanisms underlying autophagy dysregulation in cancer cachexia and the potential for autophagy-based interventions to improve patient outcomes.
    Keywords:  Autophagy; Cancer cachexia; Diet therapy; Exercise; Liver metabolism; Mitophagy; Muscle wasting; Tumor metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.008
  39. J Control Release. 2026 Jun 06. pii: S0168-3659(26)00484-0. [Epub ahead of print] 115081
    Targeted degradation of intracellular organelles: Strategies and implications.
    Yifei Lu, Yunting Zhang, Keran Wang, Renhe Liu, Yao Fu.
      Organelle dysfunction is increasingly recognized as a primary driver of neurodegeneration, metabolic disorders, and cancer. The selective elimination of these organelles is primarily mediated by the autophagy-lysosome pathway. Targeted organelle degradation (TOD) has thus emerged as a powerful strategy to harness and redirect this machinery, enabling the selective clearance of organelles through engineered cargo recognition and lysosomal delivery. In this review, we aim to establish a mechanism-driven classification framework for TOD. We comprehensively survey current strategies and systematically integrate representative modalities, including autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), nanoparticle-based organelle targeting chimeras (NanoTACs), and related platforms within this framework. Key experimental strategies for assessing degradation efficiency are critically compared, with a particular focus on mitochondria and lipid droplets as well-developed case studies. Finally, we discuss the potential for expanding TOD to other organelles such as the endoplasmic reticulum and Golgi apparatus, and we highlight key challenges and future directions to drive continued advancement in the field.
    Keywords:  ATTEC; AUTAC; Lipophagy; Mitophagy; NanoTAC; Selective autophagy; Targeted organelle degradation
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115081
  40. Inflamm Res. 2026 Jun 11. pii: 138. [Epub ahead of print]75(1):
    From lipid overload to autophagy collapse: how lipid dysregulation drives chronic inflammation and metabolic disease.
    Mykyta Fomin, Konstantin Zapf, Elisabeth Schieffer, Johannes Freitag, Gert Bange, Bernhard Schieffer.
       INTRODUCTION: Autophagy is a central homeostatic mechanism that preserves intracellular quality control by clearing damaged organelles, aggregated proteins, and excess lipids. Increasing evidence indicates that the lipid-autophagy axis is a critical determinant of chronic inflammatory and metabolic disease. Cholesterol-rich and oxidatively modified lipoproteins, including very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), oxidized LDL, and lipoprotein(a), can impose lysosomal stress, disturb autophagosome maturation, and amplify oxidative and inflammatory signaling, whereas high-density lipoprotein-mediated cholesterol efflux supports cellular lipid clearance and autophagic competence. When chronic lipid overload exceeds lysosomal and autophagic capacity, cells transition from adaptive lipophagy to impaired autophagic flux, leading to lipid-droplet accumulation, mitochondrial dysfunction, inflammasome activation, and sustained cytokine production. This review synthesizes mechanistic insights linking lipid dysregulation and autophagy failure across atherosclerosis, metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), and neurocognitive disorders. We further discuss how defective autophagy impairs efferocytosis, phagosome maturation, and inflammasome restraint, thereby contributing to unresolved inflammation and inflammatory cell-death signaling. Translationally, we outline therapeutic strategies that combine metabolic unloading, lipid-lowering interventions, autophagy-lysosome modulation, and flux-based biomarker approaches.
    CONCLUSION: Lipid-induced autophagic flux failure provides a unifying framework for understanding how metabolic stress evolves into chronic inflammation and organ dysfunction and identifies actionable targets for precision therapeutic intervention.
    Keywords:  Autophagy; Cholesterol fractions; Diseases; Inflammation; Lipid metabolism; Pathway analysis
    DOI:  https://doi.org/10.1007/s00011-026-02283-w
  41. Exp Neurol. 2026 Jun 12. pii: S0014-4886(26)00240-2. [Epub ahead of print] 115875
    HSPA1-regulated mitophagy-necroptosis crosstalk determines the fate of brain microvascular endothelial cells after cerebral ischemia.
    Qiuyue Yang, Yuxiang Wu, Hui Zhao, Qiuxia Zhang.
      Ischemic stroke triggers brain microvascular endothelial dysfunction. Necroptosis (RIP3-MLKL) and PINK1-Parkin mitophagy are both implicated, but their coordination and the role of HSPA1/HSP70 remain unclear. Using oxygen-glucose deprivation (OGD) in hCMEC/D3 cells and a rat permanent middle cerebral artery occlusion (pMCAO) model, we tested whether stress-inducible HSPA1 mediates a mitochondrial "tug-of-war" between necroptosis and mitophagy. Time-course analysis identified a 4-h OGD window in which RIP3/MLKL activation and mitochondrial MLKL oligomerization peaked, while PINK1-Parkin and HSPA1 increased later. Within this window, necrostatin-1 (Nec-1) suppressed RIP3/MLKL signalling and mitochondrial MLKL oligomers, improved cell viability, and partially reshaped mitophagy markers. Rapamycin (RAPA) improved viability, upregulated PINK1, LC3-II/LC3-I and HSPA1, and reduced mitochondrial MLKL oligomers despite increased total RIP3/MLKL, consistent with enhanced autophagy and attenuated necroptotic execution. The mitochondrial HSP70 inhibitor MKT-077 reduced both MLKL oligomers and PINK1, suggesting that both pathways may be influenced by HSPA1-related activity. In pMCAO rats, Nec-1 and MKT-077, and to a lesser extent RAPA, improved neurological outcomes and reduced infarct volume; immunofluorescence further revealed increased necroptosis- and mitophagy-related signals in the peri-infarct cortex, with overlapping MLKL and PINK1 signals observed in CD31-positive endothelial cells/microvascular structures. Collectively, HSPA1 may function as a shared and limited chaperone resource that shifts from supporting necroptosis early to facilitating mitophagy as its abundance rises, thereby protecting endothelium after cerebral ischemia.
    Keywords:  Brain microvascular endothelial cells; Cerebral ischemia; HSPA1/HSP70; Mitophagy; Necroptosis
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115875
  42. PLoS One. 2026 ;21(6): e0350815
    UBC/UBA52 silencing restores PINK1-Parkin-mediated mitochondrial autophagy in allergic rhinitis.
    Qinhui Lu, Yanli Yang, Biao Ruan.
      Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract, and recent studies suggest that mitochondrial dysfunction may play a role in its pathogenesis. This study aimed to identify key genes related to AR and mitochondrial autophagy through bioinformatics analysis and to verify their functional roles in vitro. Transcriptomic data from the GEO database were analyzed, and ubiquitin C (UBC) and ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52) were identified as potential genes associated with AR and mitophagy. In vitro, IL-13-stimulated human nasal epithelial cells (HNEpCs) were used to establish an AR model. RT-qPCR and Western blotting showed that UBC and UBA52 were significantly upregulated, while mitophagy-related genes PINK1 and Parkin were downregulated. Flow cytometry and TMRE staining demonstrated increased ROS levels and reduced mitochondrial membrane potential (MMP), indicating mitochondrial dysfunction. Co-immunoprecipitation confirmed an interaction between UBC and UBA52. Silencing UBC downregulated UBA52 expression, restored PINK1 and Parkin levels, decreased ROS accumulation, and improved MMP, suggesting potential reactivation of the PINK1-Parkin-mediated mitophagy pathway. These findings suggest that UBC and UBA52 may be involved in the regulation of mitophagy and contribute to mitochondrial dysfunction in AR. Targeting the UBC-UBA52 axis may provide a novel therapeutic strategy for restoring mitochondrial homeostasis in allergic inflammation.
    DOI:  https://doi.org/10.1371/journal.pone.0350815
  43. JCI Insight. 2026 Jun 08. pii: e198505. [Epub ahead of print]11(11):
    LDL receptor-mediated lipoprotein uptake fuels human CD4+ T cell polarization toward a c-MAF/IL-10- and FOXP3-driven phenotype.
    Angela Markovska, Niels S van Heusden, Dagmar Duijzer, Alejandra Bodelón, Greta Rogani, Enric Mocholi, Edwin Ca Stigter, Can Gulersonmez, Sander Kooijman, Leonie Van der Zee, Monique T Mulder, Jeanine E Roeters van Lennep, Patrick Cn Rensen, Jorg van Loosdregt, Sebastiaan J Vastert, Noam Zelcer, Marianne Boes, Henk S Schipper.
      Human CD4+ T cells utilize nutrients, including lipids, to support their activation and polarization. Considering the pivotal role of lipoproteins in lipid transport, we reasoned that lipoprotein uptake and processing could effect CD4+ T cell function. Here, we demonstrate that activation of human CD4+ T cells induced expression of LDL receptor (LDLR) to facilitate LDLR-mediated endocytosis of LDL. Degradation of surface LDLR on CD4+ T cells with PCSK9 hampered activation and proliferation of the cells. Lipoprotein deprivation or blocking of lysosomal cholesterol egress impaired activation of mechanistic target of rapamycin complex 1 (mTORC1), affecting CD4+ T cell activation and proliferation. Furthermore, lipoprotein deprivation of cultured primary CD4+ T cells lead to reduced expression of c-MAF and FOXP3, key transcription factors for IL-10, accompanied by reduced IL-10 secretion. The pivotal role of LDLR-mediated lipoprotein uptake for mTORC1 activity, c-MAF and FOXP3 expression, and IL-10 secretion was confirmed using LDLR-dysfunctional CD4+ T cells from patients with homozygous familial hypercholesterolemia. Our study offers valuable insights into the lipoprotein metabolism of human CD4+ T cells and their reliance on the LDLR pathway for activation and polarization, a feature that may be leveraged to modulate CD4+ T cell function.
    Keywords:  Cell biology; Immunology; Lipoproteins; T cells
    DOI:  https://doi.org/10.1172/jci.insight.198505
  44. FASEB J. 2026 Jun 30. 40(12): e71837
    IRF-1 Links Cytoskeletal Contraction With Inflammatory Response in mTOR-Inhibited Endothelial Cells.
    Ying Zhou, Zhiyang Zhang, Chengxiu Hu, Xiangjun Zhu, Xing Fan, Dai-Min Zhang, Anthony G Passerini, ChongXiu Sun.
      Clinical therapies targeting mammalian target of rapamycin (mTOR) are associated with high rates of pneumonitis. Recent studies independently revealed the upregulation of the proinflammatory transcription factor interferon regulatory factor-1 (IRF-1) by mTOR inhibition (mTORi) of endothelial cells (EC) and further highlighted a mechanism converging on myosin light chain (MLC) phosphorylation-dependent cytoskeletal dynamics in promoting the endothelial hyperpermeability and pulmonary inflammation caused by mTORi. This study investigated a role for this mechanism in linking the regulation of IRF-1 expression with downstream responses in mTOR-inhibited EC. IRF-1 was transcriptionally upregulated in cultured EC by treatment with mTOR inhibitor rapamycin or torin 1, or by silencing either Raptor or Rictor expression to disrupt mTOR complex 1 (mTORC1) or 2 (mTORC2). Inhibition of MLC kinase (MLCK) activity or activation of MLC phosphatase (MLCP) to suppress MLC phosphorylation, or direct inhibition of actin polymerization, attenuated IRF-1 expression as well as transcription of an array of proinflammatory cytokines. Moreover, IRF-1 in turn upregulated MLCK expression to enhance MLC phosphorylation and promote endothelial hyperpermeability in mTOR-inhibited EC. Consistent with these observations in culture, targeted endothelial deficiency of IRF-1 in mice significantly reduced lung edema and inflammation elicited by separate or combined treatment of rapamycin and lipopolysaccharide. In conclusion, activation of actomyosin contractility by mTORi upregulated IRF-1, which promoted the development of lung injury by mediating inflammation and hyperpermeability responses in EC.
    Keywords:  actin cytoskeleton; cell contraction; endothelial cell; inflammation; lung injury; mTOR inhibition; myosin light chain; permeability
    DOI:  https://doi.org/10.1096/fj.202503788R
  45. J Biochem Mol Toxicol. 2026 Jun;40(6): e70952
    Dynorphin B Promotes Autophagy and Cytotoxicity in Thyroid Cancer Cells via the mTORC1-TFE3 Axis.
    Xuesong Wu, Xuesong Zhai, Lizhen Ren, Dongguang Qin, Wei Ding.
      Autophagy can either support tumor survival or induce cell death in thyroid cancer. This process is a promising therapeutic target. This study aimed to investigate the effects and molecular mechanisms of Dynorphin B in TPC-1 thyroid cancer cells. Dynorphin B, an endogenous opioid peptide, triggers autophagic flux. It increases LC3-II/I ratios and p62 degradation. Autophagosome formation rises, confirmed by monodansylcadaverine staining. Dynorphin B also induces dose-dependent cytotoxicity. It disrupts mitochondrial membrane potential and ATP production. Oxidative stress increases, marked by elevated 8-OHdG levels and reduced SOD activity. Mechanistically, Dynorphin B inhibits mTORC1 activity. This reduces p-S6K phosphorylation levels. TFE3 dephosphorylation at Ser321 occurs. TFE3 translocates to the nucleus, activating transcription of autophagy genes ATG5 and LC3. Lysosomal genes LAMP1 and CTSD are also upregulated. TFE3 knockdown blocks these effects, confirming its essential role. Chromatin immunoprecipitation shows TFE3 binding to CLEAR motifs in ATG5 and p62 promoters. Luciferase assays validate CLEAR gene activation. Clinically, immunohistochemical evaluation of biopsy specimens demonstrated markedly lower KOR-1 expression in malignant thyroid tissues than in adjacent normal tissues. These findings reveal that Dynorphin B modulates autophagy and cytotoxicity through the mTORC1-TFE3 axis, indicating its potential to regulate thyroid cancer cell fate.
    Keywords:  Dynorphin B; TFE3; autophagy; mTORC1; thyroid cancer
    DOI:  https://doi.org/10.1002/jbt.70952
  46. Mol Med. 2026 Jun 09.
    A peptide-induced regression of low-grade malignant breast tumor via activation of autophagy in breast cancer cells.
    Saibal Saha, Rishikesh Kumar, Snehanjan Sarangi, Animesh Gope, Ananda Pal, Rima Tapader, Niraj Nag, Sushmita Bhattacharya, Amit Pal.
      Peptides have recently gained much attention for their therapeutic role in several diseases without having significant side effects. These are short chain amino acids and can be synthesized chemically with a great extent of purity, which renders them very effective, precise and safe for the body. So far, very few artificially synthesized peptides have been developed that have autophagy-inducing properties. Among them, a very small number of peptides have been demonstrated to have anti-tumorigenic effect by modulating autophagy with most of them lacking specificity for target cells. This study aims to investigate the regulation of autophagy through noncanonical activation of protease-activated receptor 1 (PAR1) by hemagglutinin protease (HAP). Unlike the canonical activation of PAR1 by thrombin, which enhances cell proliferation via mechanistic target of rapamycin (mTOR) signaling, HAP-induced noncanonical activation downregulates mTOR activation and triggers autophagy in both estrogen receptor positive/ progesterone receptor positive/ HER2 negative (ER+/PR+/HER2-) and triple negative (ER-/PR-/HER2-) breast cancer cells. This noncanonical activation generates a N-terminal sequence in PAR1. When this sequence is mimicked by a synthetic peptide, it induces autophagy independently of HAP in the breast cancer cells in vitro. Further in vivo investigation in BALB/c mouse model of low-grade malignant breast tumor reveals that the peptide-induced autophagy significantly inhibits tumor growth and delays tumor progression. Importantly, the lack of PAR1 expression in normal, healthy breast epithelial cells facilitates the peptide to selectively target breast cancer cells with relatively high PAR1 expression, highlighting its potential as a therapeutic agent against low-grade malignant breast tumor. These findings provide valuable insights into autophagy activation by a synthetic peptide that targets breast cancer cells with high PAR1 expression and for the first time shows peptide mediated targeted therapy of low-grade malignant breast tumor.
    Keywords:  Hemagglutinin protease; Peptide; Peptide-induced autophagy; Protease-activated receptor 1
    DOI:  https://doi.org/10.1186/s10020-026-01514-4
  47. J Lipid Res. 2026 Jun 12. pii: S0022-2275(26)00103-3. [Epub ahead of print] 101077
    Ceramide kinase/ceramide 1-phosphate signaling regulates LC3B expression and autophagosome formation.
    Hideki Funou, Natsuka Arai, Shimon Nakajima, Ryo Kadowaki, Kenta Nakamaura, Miaki Uzu, Takuya Honda, Hiroyuki Nakamura.
      Ceramide kinase (CerK) generates ceramide 1-phosphate (C1P), a bioactive sphingolipid involved in diverse cellular responses, but its role in autophagy is not fully understood. Here, we examined whether the CerK/C1P pathway regulates LC3B expression and autophagosome formation in HeLa cells. Proteomics analysis of cerebellum from Cerk-KO mice identified reduced levels of multiple autophagy-related proteins. In HeLa cells, genetic ablation, siRNA-mediated knockdown, and pharmacological inhibition of CerK consistently reduced LC3B-II levels. This effect was reversed by extracellular C1P and by re-expression of wild-type, but not kinase-dead, CerK, indicating that CerK-generated C1P is required for maintenance of LC3B-II. LC3B-II levels remained lower in CERK-KO cells in the presence of bafilomycin A1, and two-step flux analysis showed that disruption of the CerK/C1P pathway preferentially impaired the LC3B-associated autophagosome formation parameter. MAP1LC3B mRNA and Nrf2 protein levels were reduced in CERK-KO cells, and pharmacological activation of Nrf2 tended to restore MAP1LC3B mRNA levels and significantly increased LC3B-II protein levels. Finally, loss of the CerK/C1P pathway enhanced nutrient starvation-induced apoptotic responses and loss of viability. Together, these results identify the CerK/C1P pathway as a positive lipid signaling mechanism that maintains LC3B expression, supports LC3B-associated autophagosome formation, and promotes cell survival under nutrient-deprived conditions.
    Keywords:  Autophagosome formation; Cell signaling; Ceramide 1-phosphate; Ceramide kinase; Ceramides; Golgi apparatus; LC3B; Nrf2; Proteomics; Sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2026.101077
  48. Nat Commun. 2026 Jun 10.
    Discovery of a snail hibernation-inducer offering hibernation-like cardioprotection through metabolic rewiring and autophagy in mice.
    Jiyuan Piao, Yongneng Zhang, Yuan-Yuan Zhao, Patrick Hanington, Jacob Hambrook, Yongsheng Liu, John R Ussher, Seyed Amirhossein Tabatabaei Dakhili, Gopinath Sutendra, Evangelos D Michelakis.
      Hibernating animals achieve cellular dormancy through metabolic remodelling and autophagy, resisting ischemic and ischemia-reperfusion (IR) injury, while non-hibernators are vulnerable to both. Here we describe the discovery of a circulating dormancy-inducing factor in hibernating snails, which we synthesized chemically and because it activates PHLPP1 (a phosphatase regulating AKT and mTORC1/S6K1), named it SNail Activator of PHLPP1 (SNAP). During IR, plasma membrane PHLPP1 and p-AKT translocate to the cytoplasm and mitochondria, where SNAP dephosphorylates mitochondrial p-AKT and cytoplasmic p-S6K1, inducing dormancy in snails and promoting autophagy, reversible cell-cycle exit, proteostasis and apoptosis-resistance in IR-stressed mouse fibroblasts. In IR models of cardiomyocytes and perfused hearts, SNAP is cardioprotective by inducing autophagy, preserving Pyruvate Dehydrogenase (PDH) activity, preventing mitochondrial depolarization and ROS-induced ER stress. SNAP's cardioprotective mitochondrial effects are absent in hearts with a cardiomyocyte-specific PDH knockout. SNAP reveals fundamental mechanisms of cellular stress protection and may be beneficial in the IR injury of normal hearts offered for transplantation, a major clinical challenge.
    DOI:  https://doi.org/10.1038/s41467-026-74208-4
  49. Fundam Res. 2026 May;6(3): 1893-1912
    Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
    Yu Zhang, Xishui Liu, Zijie Xiang, Yuqing Yang, Lei Xing, Yu Chen, Siming Zhang, Shixiang Zhao, Youzhi Hong, Yusen Qiao, Jiaxiang Bai.
      Mitochondria have complex functional and information-processing networks that play key roles in both health regulation and disease progression. However, the multiple properties and complex thresholds of mitochondrial dysfunction and quality control make the contribution of mitochondria to bone aging elusive. These factors prevent mitochondria from being among the most important precision therapies. Currently, many strategies that target mitochondrial homeostasis have entered clinical trials. In mitochondria, mitochondrial DNA (mtDNA) and its associated proteins are potential therapeutic agents for immunometabolic diseases and tissue injury, with the aim of enhancing mitochondrial function. Here, we comprehensively review the intrinsic mechanisms of mitochondrial dysfunction and quality control leading to bone aging and summarize current strategies for the treatment of skeletal aging disorders and the clinical translation of relevant agents in terms of unraveling dysfunctional pathways and developing precision therapies. In this review, we offer a general overview of the progress of clinical application in the treatment of skeletal senescence diseases, and we also provide prospects for the challenges associated with the role of mitochondrial dysfunction in bone senescence in clinical application and future trends in this field.
    Keywords:  Bone aging; Clinical application; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Precision therapy; Quality control
    DOI:  https://doi.org/10.1016/j.fmre.2025.12.021
  50. J Virol. 2026 Jun 12. e0043426
    Cleavage of TOM1 by the SARS-CoV-2 main protease NSP5 prevents autophagic degradation of viral envelope.
    Qingxiang Zhang, Jingguo Xin, Chunlei Wang, Xue Zhang, Yuan Gao, Wenying Gao, Wenyan Zhang.
      Autophagy plays a critical role in viral replication and the regulation of host immune responses. Although the TOM1-TOLLIP complex has been implicated in immune signaling, cargo trafficking, and endocytosis, its role in viral replication has not been defined. Here, we demonstrate that the SARS-CoV-2 main protease (NSP5) cleaves TOM1 at residue Q354 through its protease activity. This cleavage is also observed with the main proteases of SARS-CoV and MERS-CoV. Importantly, TOM1 overexpression suppresses SARS-CoV-2 replication in HEK293T-hACE2 and Vero cells, while TOM1 knockout via CRISPR-Cas9 significantly enhances viral propagation, indicating that TOM1 functions as a novel restriction factor against SARS-CoV-2 infection. Moreover, various TOM1 orthologs from diverse species, including cattle, bats, monkeys, mice, and ducks, show similar restriction to SARS-CoV-2, but they all are antagonized by NSP5 cleavage. Mechanistically, we found that TOM1 recruits the autophagy receptor TOLLIP to target SARS-CoV-2 envelope (E) protein for autophagic degradation, thereby limiting viral replication. These findings highlight the importance of the TOM1-TOLLIP complex in host defense and discover that SARS-CoV-2 exploits a conserved NSP5-mediated TOM1 cleavage mechanism to evade host antiviral defenses.IMPORTANCEViruses must overcome the body's natural defenses in order to replicate and spread. One important cellular defense mechanism is autophagy, a process that helps cells remove harmful proteins and pathogens. In this study, we discovered that a host protein called TOM1 acts as a restriction factor that helps limit the replication of SARS-CoV-2, the virus responsible for COVID-19. TOM1 works together with another protein, TOLLIP, to direct envelope proteins to the cell's degradation system, thereby reducing viral replication. However, SARS-CoV-2 has evolved a strategy to counter this defense. The viral main protease (NSP5) cleaves TOM1, disabling its antiviral activity. This mechanism is conserved among several coronaviruses, including SARS-CoV and MERS-CoV. Our findings reveal a previously unrecognized antiviral role of the TOM1-TOLLIP complex and demonstrate how coronaviruses evade this host defense, providing new insight into virus-host interactions and potential targets for antiviral therapies.
    Keywords:  NSP5 protease; SARS-CoV-2; TOLLIP; TOM1; cleavage
    DOI:  https://doi.org/10.1128/jvi.00434-26
  51. Virol Sin. 2026 Jun 09. pii: S1995-820X(26)00094-5. [Epub ahead of print]
    RNF26 Bridges ER Stress and Autophagy in the Clearance of MERS Envelope protein.
    Ziyue Li, Yang Wang, Jingbo Qie, Shuangqu Li, Zhaobing Gao, Hin Chu, Bingqing Xia.
      Coronavirus envelope (E) proteins are small, highly conserved viroporins essential for virion assembly and pathogenicity. Despite extensive characterization of their ion channel activity, how host cells sense and dispose of excessive viral membrane proteins remains poorly understood. Here we show that expression of the MERS-CoV E protein triggers pronounced ER stress and autophagy activation in human cells. The E protein is selectively degraded through an RNF26-dependent autophagy-lysosome pathway, and inhibition of autophagy or loss of RNF26 function leads to E accumulation and sustained unfolded protein response. Mechanistically, RNF26, an ER-anchored E3 ubiquitin ligase, promotes RING-dependent clearance of the viral protein through an ER protein quality control-associated pathway linked to autophagy and ER stress adaptation. Disruption of this process establishes a self-amplifying ER stress-autophagy feedback loop that exacerbates proteotoxicity. These findings define a membrane homeostatic conflict between viral viroporins and the host defense machinery, and identify RNF26 as a potential therapeutic target for mitigating viroporin-induced cytotoxicity through host-directed intervention.
    Keywords:  Autophagy; Cellular stress response; Coronavirus envelope (E) proteins; Host-virus interaction; Pathogenicity
    DOI:  https://doi.org/10.1016/j.virs.2026.06.005
  52. Sci Rep. 2026 Jun 08. pii: 18028. [Epub ahead of print]16(1):
    Canonical autophagy remains inactive in induced pluripotent stem cells and neuronal progenitor cells following DNA damage induced by BPDE or etoposide.
    Seda Akgün, Padmashri Naren, Thomas Lenz, Annika Zink, Karina Stephanie Krings, Sebastian Wesselborg, María José Mendiburo, Alessandro Prigione, Kai Stühler, Björn Stork.
      (Macro-)Autophagy is a key cellular stress response mediating the recycling of long-lived or damaged proteins and organelles. In stem cells, autophagy is essential for the decision between quiescence, self-renewal and differentiation. We observed that induced pluripotent stem cells (iPSCs) and thereof derived neural progenitor cells (NPCs) have a functional autophagy machinery, as shown by starvation-induced autophagic flux and ULK1 activation. Using the human iPSC lines iPS11 and iPS12 and thereof derived NPCs (niPS11 and niPS12), we investigated whether genotoxic stress induced by low doses (IC20) of benzo[a]pyrene diolepoxide (BPDE) or etoposide can similarly activate autophagy, as previously reported for cancer cell lines. While both BPDE and etoposide induced the DNA damage markers phospho-p53 Ser15 and γH2AX and slightly altered the expression of DNA repair proteins such as XPC, they did not trigger autophagic flux in either iPSCs or NPCs. After genotoxin treatment, ULK1 activation was only observed in NPCs, but this was not sufficient to trigger a significant downstream autophagic response. Mass spectrometry revealed minimal proteomic changes in iPSCs and moderate changes in NPCs, mainly involving mitotic regulators. In summary, no significant activation of canonical autophagy was detectable in iPSCs and NPCs within the tested time frame and under low-dose genotoxic conditions, although both cell types retain a functional autophagic machinery.
    Keywords:  Autophagy; BPDE; Etoposide; NPC; iPSC
    DOI:  https://doi.org/10.1038/s41598-026-54127-6
  53. Diabetologia. 2026 Jun 09.
    Fetal growth is driven by a bimodal fetal beta cell response and reshaped by a ketogenic diet in a mouse model of maternal diabetes.
    Omer Cohenshtam, Amnon Zung, Amy Yu, Hadar King, Polina Kotova, Ofer Gover, Itia Magenheim Samuel, Sarit Helman, Michael D Walker, Danny Ben-Zvi, Naama Kanarek, Aharon Helman.
       AIMS/HYPOTHESIS: Maternal diabetes confers two opposing risks to fetal growth, resulting in macrosomia in mild cases and intrauterine growth restriction (IUGR) in severe cases. The mechanisms governing these divergent responses are poorly understood, given the intimate regulation of insulin by glucose and insulin's fetal growth-promoting effects. We hypothesised that the degree of maternal hyperglycaemia dictates a bimodal pattern of fetal insulin secretion that determines fetal growth, and that use of a ketogenic diet (KD) as a nutritional intervention could modify this outcome.
    METHODS: We used the Insulin-rtTA;TET-DTA mouse model to induce preconception diabetes. Dams were stratified based on maternal blood glucose, namely non-diabetes (glucose <9.6 mmol/l), mild diabetes (glucose range 9.6-16.7 mmol/l) or severe diabetes (glucose >16.7 mmol/l), and maintained on either a normal diet or a KD. We assessed fetal growth and plasma C-peptide, performed islet functional assays ex vivo, and characterised changes in plasma metabolites. Fetal pancreases were analysed by immunohistochemistry for beta cell area, proliferation, maturation and mechanistic target of rapamycin complex 1 (mTORC1) activity.
    RESULTS: Mild maternal diabetes induced fetal macrosomia, driven by beta cell hyperplasia, hyperinsulinaemia and premature beta cell functional maturation, as reflected by glucose-stimulated insulin secretion and upregulated MafA expression. This was associated with strong activation of the mTORC1 pathway. In contrast, severe diabetes caused IUGR associated with reduced beta cell mass and profound functional impairment. The KD had divergent effects: it normalised fetal growth in the mild diabetes group by preventing beta cell proliferation and premature maturation, thereby reducing insulin secretion, but failed to rescue IUGR in the severe diabetes group, despite partially restoring beta cell function. Notably, the KD uncoupled the positive correlation between fetal insulin and body weight, revealing a primary, insulin-independent, growth-restrictive effect.
    CONCLUSIONS/INTERPRETATION: Fetal growth in a mouse model of diabetes in pregnancy is governed by a bimodal beta cell response to the maternal glycaemic environment, orchestrated at the molecular level by the mTORC1 pathway. A KD can prevent diabetes-derived macrosomia by reducing beta cell stimulation and through insulin-independent mechanisms, but cannot reverse IUGR, warranting further studies of its role in diabetes during pregnancy.
    Keywords:  Beta cell maturation; Fetal beta cell; Fetal growth; IUGR; Insulin secretion; Ketogenic diet; Macrosomia; Maternal diabetes; Pregnancy; mTORC1
    DOI:  https://doi.org/10.1007/s00125-026-06771-w
  54. Biomed Pharmacother. 2026 Jun 12. pii: S0753-3322(26)00688-8. [Epub ahead of print]201 119652
    Selective HDAC6 inhibition perturbs autophagy and enhances integrated stress response-mediated immunogenic apoptosis in chronic myeloid leukemia.
    Ji Yeon Paik, Sruthi Reddy Gajulapalli, Vladimir Li, Sujung Park, Yejin Lee, Barbora Orlikova-Boyer, Anne Lorant, Christo Christov, Gilbert Kirsch, Hyoung Jin Kang, Michael Schnekenburger, Claudia Cerella, Marc Diederich.
      Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion oncoprotein and is managed with tyrosine kinase inhibitors (TKIs). However, resistance and persistence of leukemic stem/progenitor cells remain major clinical challenges. Autophagy-mediated survival signaling contributes to therapeutic resistance in CML. We hypothesized that histone deacetylase 6 (HDAC6), a key regulator of protein homeostasis and autophagic flux, is a therapeutic target in this context. Transcriptomic analysis of CML bone marrow datasets revealed enrichment of HDAC6-associated autophagy and stress-response gene programs. The selective HDAC6 inhibitor 7b induced sustained α-tubulin acetylation at lower concentrations than ricolinostat or nexturastat A. 7b reduced primary CML PBMC viability while sparing healthy PBMCs and was active in vivo. Combining 7b with the allosteric BCR-ABL1 inhibitor asciminib synergistically suppressed cell viability and clonogenic growth. A tandem mCherry-GFP-LC3 reporter showed that 7b blocks autophagosome maturation, thereby decreasing autophagic degradation. Cotreatment engaged a maladaptive integrated stress response (ISR), characterized by eIF2α phosphorylation, ATF4 and CHOP induction, MCL-1 suppression, PUMA and NOXA upregulation, and BCL-xL-dependent mitochondrial apoptosis, accompanied by caspase-2 activation. ISR activation occurred downstream of the autophagy disruption: rapamycin attenuated ISR activation, whereas ATG7 silencing intensified ISR signaling and apoptosis. CHOP knockdown blunted the BCL-xL/PUMA/NOXA shift and caspase-3 cleavage, establishing CHOP as required. Caspase-10 acted upstream of caspases-9, -7, and -3. The combination elicited immunogenic cell death markers: calreticulin exposure, ATP and HMGB1 release, elevated TNF-α, and reduced IL-8. These findings identify HDAC6-driven autophagy as a therapeutically exploitable vulnerability in CML that, when combined with asciminib, triggers ISR-dependent immunogenic apoptosis.
    Keywords:  Asciminib; Autophagy; Caspase-dependent apoptosis; Chronic myeloid leukemia; ER stress; HDAC6; Immunogenic cell death; Integrated stress response
    DOI:  https://doi.org/10.1016/j.biopha.2026.119652
  55. Autophagy. 2026 Jun 12. 1-3
    Cell stress and death liberate the autophagy-inhibitory tissue stress hormone DBI/ACBP into the circulation.
    Yan Rong, Flavia Lambertucci, Yaning Yang, Yanbing Dong, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer.
      Autophagy constitutes a major adaptive response that preserves cellular and organismal homeostasis during stress. However, stress responses also engage systemic communication pathways that may either maintain resilience or propagate pathology. We previously identified acyl-CoA-binding protein, also known as diazepam-binding inhibitor (DBI/ACBP), as a phylogenetically conserved extracellular factor secreted by stressed cells through an unconventional autophagy-dependent pathway. Once released, extracellular DBI/ACBP acts as a feedback inhibitor of autophagy and promotes metabolic and inflammatory alterations. In our most recent work, we identify regulated cell death as an additional major mechanism responsible for extracellular DBI/ACBP accumulation. Plasma DBI/ACBP concentrations correlate with markers of inflammation, senescence and multiorgan dysfunction in hospitalized patients. Experimentally induced injury to liver, kidney, pancreas or skeletal muscle indistinguishably causes rapid increases in circulating DBI/ACBP. Mechanistically, apoptosis, ferroptosis and necroptosis all provoke loss of intracellular DBI/ACBP together with its extracellular release following plasma membrane permeabilization. Pharmacological inhibition of these death pathways suppresses DBI/ACBP liberation. Across large human cohorts, elevated plasma DBI/ACBP is associated with aging, systemic inflammation, multiorgan dysfunction and future morbidity. We propose that DBI/ACBP is not merely a biomarker of tissue damage but rather a systemic autophagy-inhibitory stress signal contributing to maladaptive interorgan communication during aging and disease.
    Keywords:  Aging; disease; mortality; organ failure; stress
    DOI:  https://doi.org/10.1080/15548627.2026.2685761
  56. Int Immunopharmacol. 2026 Jun 12. pii: S1567-5769(26)00830-1. [Epub ahead of print]185 116984
    Galectin-1 exacerbates hepatic steatosis by impairing autophagy via interaction with FIP200.
    Lujuan Zheng, Jing Xia, Pengyu Ge, Jiaxing Sheng, Min Wang, Junzhu Wei, Yanchen Qi, Yueming Ma, Xinbin Zhao, Chengcheng Song, Yuying Fan, Yifa Zhou.
      The pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains incompletely understood, particularly the regulatory mechanisms linking autophagy dysregulation to disease progression. While impaired hepatic autophagy is known to contribute to NAFLD, the upstream factors that suppress autophagic flux under metabolic stress are not well defined. In this study, we demonstrate that galectin-1 (Gal-1) acts as a key mediator of hepatic steatosis and metabolic dysfunction by directly inhibiting autophagy. Surprisingly, overexpression of Gal-1 in mice is sufficient to trigger a series of pathological features similar to those of NAFLD, including hepatic steatosis, dyslipidemia, and insulin resistance, even in the absence of dietary challenges. Proteomic profiling revealed that Gal-1 induces a pronounced blockade of autophagic flux, evidenced by p62 accumulation and impaired LC3-II conversion. Mechanistically, Gal-1 binds the core autophagy scaffold protein FIP200, disrupting ULK complex assembly and further suppressing FIP200 expression at both transcriptional and post-translational levels. Structural mapping and binding studies identified a specific bipartite interaction interface involving Gal-1 residues TYR120/PHE134 and the claw domain of FIP200, with a binding affinity (Kd = 113.1 μM) critical for its autophagy-inhibitory function. Crucially, point mutations disrupting this interaction abolished Gal-1-mediated autophagy suppression and insulin resistance in cellular models. Our results uncover the Gal-1-FIP200 axis as a previously unrecognized regulatory node in NAFLD pathogenesis, offering a promising target for therapeutic intervention in metabolic liver disease.
    Keywords:  Autophagy; FIP200; Galectin-1; Insulin resistance; NAFLD
    DOI:  https://doi.org/10.1016/j.intimp.2026.116984
  57. Cell Death Dis. 2026 Jun 08.
    Lysine acetyltransferase 8-mediated histone acetylation, regulated by GBA1, is associated with lysosomal function related to α-Synuclein pathology.
    Yifan Cao, Zhixiong Zhang, Xinbei Gu, Haifeng Lu, Jin Wu, Chuang Zhang, Xinyue Huang, Haitao Qin, Feng Liu, Zhenhua Liu, Beisha Tang, Xiaojun Lu, Haigang Ren, Hongyang Sun, Rui Wang, Guanghui Wang.
      Lysosomal defects are closely linked to Parkinson's disease (PD). Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are major genetic risk factors for PD. GBA1 deficiency causes lysosomal dysfunction, leading to α-synuclein (α-syn) accumulation and PD progression. However, the underlying mechanisms remain unclear. In this study, we identified a novel GBA1-KAT8 regulatory pathway that controls lysosomal activity. GBA1 overexpression enhances lysosomal enzyme expression, regulates histone H4 acetylation at K16 via KAT8, and promotes lysosome-associated gene expression, highlighting an epigenetic mechanism in lysosomal biogenesis. Furthermore, GBA1 upregulated KAT8 expression, increased lysosomal enzyme levels, and decreased PFF-induced α-syn accumulation both in vitro and in vivo. The involvement of KAT8 as a critical acetyltransferase that modulates nuclear-lysosomal signaling pathways provides a mechanistic explanation for GBA1 deficiency-induced lysosomal dysfunction in association with PD pathology.
    DOI:  https://doi.org/10.1038/s41419-026-08928-2
  58. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  59. bioRxiv. 2026 Jun 06. pii: 2026.06.05.730386. [Epub ahead of print]
    Vacuole pH loss triggers ESCRT-dependent plasma membrane remodeling to prevent amino acid toxicity.
    Kevin C Chui, Casey E Hughes, Troy K Coody, Adam L Hughes.
      Loss of lysosomal or vacuolar acidity is a hallmark of aging, metabolic dysfunction, and cellular stress, yet how cells adapt to this condition remains poorly understood. In budding yeast, where the vacuole serves as a major reservoir for intracellular amino acids, impaired vacuolar acidification disrupts amino acid homeostasis. Here we performed a genome-wide screen in budding yeast to identify pathways required for survival during vacuole pH stress. We found that endocytic trafficking and ESCRT/MVB components become essential when vacuolar acidification is disrupted. Vacuole deacidification triggered ESCRT-dependent rerouting and degradation of plasma membrane amino acid transporters, thereby limiting nutrient influx. Blocking this response stabilized transporters at the cell surface and caused synthetic lethality under vacuole stress. This growth defect was suppressed by lowering amino acid availability or reducing transporter expression, whereas amino acid supplementation restored toxicity. Nitrogen starvation prevented transporter internalization, indicating that nutrient status gates this adaptive response. Together, these findings reveal a vacuole-plasma membrane communication pathway that protects cells from amino acid toxicity by matching nutrient influx to vacuolar function.
    DOI:  https://doi.org/10.64898/2026.06.05.730386
  60. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2524190123
    A protective role for APP in nuclear waste clearance via lysosomal exocytosis.
    Godfried Dougnon, Takayoshi Otsuka, Yuka Nakamura, Akiko Sakai, Tomoyuki Yamanaka, Noriko Matsui, Asa Nakahara, Ai Ito, Atsushi Hatano, Masaki Matsumoto, Hironaka Igarashi, Akiyoshi Kakita, Masaki Ueno, Hideaki Matsui.
      Amyloid precursor protein (APP) is widely known for its role in Alzheimer's disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear waste material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.
    Keywords:  amyloid precursor protein; cellular homeostasis; lysosomal exocytosis; neurodegeneration; nuclear waste clearance
    DOI:  https://doi.org/10.1073/pnas.2524190123
  61. Redox Biol. 2026 Jun 05. pii: S2213-2317(26)00245-4. [Epub ahead of print]95 104247
    Mitophagy-mediated immune evasion: Shared strategies of pathogens.
    Jun Li, Weijian Li, Dan Wang, Yulan Liu.
      Mitophagy selectively eliminates dysfunctional mitochondria, playing a pivotal role in mitochondrial quality control and cellular homeostasis. Emerging evidence reveals that certain pathogens exploit mitophagy to evade host immune defenses. Here, we provide novel insights into the regulatory mechanisms of mitophagy by integrating it with mitochondrial dynamics, and systematically review the mechanisms by which intracellular bacteria, viruses, and parasites utilize mitophagy to subvert host innate immunity. Notably, some pathogens dynamically regulate mitophagy at different infection stages to facilitate their survival, and the mitophagy show a positive correlation with mitochondrial fission/fragmentation. This review further summarizes four therapeutic strategies to counteract pathogen-induced immune evasion via mitophagy: 1) pharmacological modulation of mitophagy pathways; 2) mitochondria-targeted nanomaterials delivery systems; 3) mitochondria transplantation; 4) nanoengineered mitochondria. Moreover, two core mechanistic questions that remain to be addressed: (1) The mechanisms of time-dependent mitophagy-mediated immune evasion during infection, and (2) the mechanistic connection between mitochondrial dynamics and mitophagy. Future studies could employ label-free holographic tomography microscopy combined with artificial intelligence to visualize and quantify pathogen-induced subcellular alterations, enhancing our understanding of how mitophagy is manipulated, particularly through stage-specific regulation. These insights may open new avenues for treating infections resistant to conventional therapies.
    Keywords:  Immune evasion; Mitophagy; Pathogen infection; Therapy
    DOI:  https://doi.org/10.1016/j.redox.2026.104247
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