Autophagy [JOURNAL]
Sun
200 papers
Keeping up with ATG7: conserved functions in Atg8ylation and beyond.
Hjaltalin VJ, Ogmundsdottir MH
Autophagy · 2026 Jun · PMID 42316826 · Publisher ↗
Atg8ylation is a key step during autophagy where Atg8-family proteins are conjugated to the expanding phagophore. In addition to double-layered autophagic compartments, Atg8ylation occurs on various other cellular membra...
Atg8ylation is a key step during autophagy where Atg8-family proteins are conjugated to the expanding phagophore. In addition to double-layered autophagic compartments, Atg8ylation occurs on various other cellular membranes and is emerging as a general eukaryotic membrane-tagging system comparable to that of ubiquitin tagging of proteins. While canonical autophagy has been characterized across eukaryotes, Atg8ylation beyond canonical autophagy has mostly been explored in mammals. ATG7 is an E1-like enzyme which participates in the three-step ubiquitin-like cascade that mediates Atg8-family protein conjugation. Apart from its role in Atg8ylation, several independent functions have been reported in mammals. Exploring functions of ATG7 from an evolutionary perspective highlights that Atg8ylation on single-layer membranes is conserved across eukaryotes. Although Atg8ylation-independent functions of ATG7 remain largely unexplored outside mammals, evidence from other eukaryotic clades suggests that some of these functional roles may be conserved. In this review, ATG7 functions are organized by eukaryotic clades to gain better understanding of their evolutionary history.: AD: active domain; CASM: conjugation of Atg8 to single layer membranes; EMT: endothelial-to-mesenchymal transition; ESCRT: endosomal sorting complexes required for transport; HFD: high-fat diet; LAP: LC3-associated phagocytosis; LECA: last eukaryotic common ancestor; NTD: N-terminal domain; PE: phosphatidylethanolamine; PS: phosphatidylserine; UBL: ubiquitin-like.
Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts.
Kim S, Goldshteyn V, Arai A … +5 more , Bae EB, Whitelegge J, Shin KH, Park NH, Kim RH
Autophagy · 2026 Jun · PMID 42316434 · Publisher ↗
Bisphosphonates (BPs) are the most widely used anti-resorptive agents and first-line drugs for managing bone-related diseases, such as osteoporosis, Paget disease of bone, and bone metastatic cancer. BPs are known to inh...
Bisphosphonates (BPs) are the most widely used anti-resorptive agents and first-line drugs for managing bone-related diseases, such as osteoporosis, Paget disease of bone, and bone metastatic cancer. BPs are known to inhibit osteoclasts' functions, and recent studies have highlighted the importance of macroautophagy/autophagy in osteoclasts. However, the involvement of autophagy in BP-mediated inhibition of osteoclast functions remains unclear. In this study, we showed that BPs inhibit the bone resorptive functions of osteoclasts by blocking autophagy. At the non-apoptotic doses, zoledronic acid (ZOL) inhibited autophagy by blocking autophagic flux and delaying the degradation of autophagy-related proteins. ZOL also prevented the cleavage and secretion of secretory proteins such as CTSK, ACP5/TRAP, and MMP9 essential for bone resorption. Mechanistically, ZOL inhibits the prenylation of the RAB7 small GTPase, a key protein that is required for autolysosome formation. studies showed that osteoclast-specific conditional knockout mice exhibited osteopetrotic phenotypes. These findings provide insights into how BPs disrupt osteoclast function by blocking autophagy and suggest that targeting autophagy in osteoclasts could be a potential therapeutic approach for bone-related diseases.: ACP5/TRAP: acid phosphatase 5, tartrate resistant, ATG: autophagy related, 54 BafA1: bafilomycin A1, BECN1: beclin 1, BMM: bone marrow-derived macrophage, CQ: 55 chloroquine, CSF1/M-CSF: colony stimulating factor 1, CTSK: cathepsin K, CTX-I: C-terminal 56 telopeptide of type I collagen, FPPS: farnesyl pyrophosphate synthase, GFP: green fluorescent 57 protein, GGTI: geranylgeranyltransferase I inhibitor, LAMP1: lysosome associated membrane 58 protein 1, MAP1LC3/LC3: microtubule associated protein 1 light chain 3, MMP9: matrix 59 metallopeptidase 9, N-BPs: nitrogen-containing bisphosphonates, P1NP: procollagen type I N- 60 terminal propeptide, PGGT1B: protein geranylgeranyl transferase type I subunit beta, RABGGTB: 61 Rab geranylgeranyltransferase subunit beta, RFP: red fluorescent protein, SQSTM1/p62: 62 sequestosome 1, TNFSF11/RANKL: TNF superfamily member 11, ZOL: zoledronic acid.
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Autophagy · 2026 Jun · PMID 42311079 · Publisher ↗
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Autophagy · 2026 Jun · PMID 42304765 · Publisher ↗
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Chaperone-mediated autophagy coordinates regeneration and fibrosis resolution.
Zhang Y, Xian P, Wang J
Autophagy · 2026 Jun · PMID 42298871 · Publisher ↗
Fibrosis is increasingly viewed as a consequence of defective tissue regeneration rather than simply excessive extracellular matrix accumulation. However, the mechanisms that simultaneously regulate fibroblast activation...
Fibrosis is increasingly viewed as a consequence of defective tissue regeneration rather than simply excessive extracellular matrix accumulation. However, the mechanisms that simultaneously regulate fibroblast activation and regenerative capacity remain poorly understood. In our recent study, we identify chaperone-mediated autophagy (CMA) as a conserved regulator of fibrosis across the lung, liver, and kidney. The CMA receptor lysosome-associated membrane protein 2 (LAMP2A) is consistently downregulated in experimental and human fibrotic diseases, accompanied by reduced CMA activity. Restoration of LAMP2A expression or pharmacological activation of CMA suppresses fibroblast activation through degradation of the mechanosensitive protein integrin subunit beta 1 (ITGB1) and simultaneously enhances regenerative programs in alveolar epithelial cells, hepatocytes, and renal tubular cells. These findings suggest that CMA functions as a regenerative checkpoint that coordinates tissue repair outcomes. Beyond its established role in proteostasis, CMA may determine whether injured tissues undergo successful regeneration or progress toward fibrosis, highlighting CMA activation as a potential therapeutic strategy for chronic fibrotic diseases. CMA: chaperone-mediated autophagy ITGB1: integrin subunit beta 1 LAMP2A: lysosome associated membrane protein 2.
SNCA/synuclein alpha impairs endometrial receptivity in obesity by disrupting STUB1-TFEB-mediated autophagy.
Tang F, Guo P, Wang L … +11 more , Xie P, Wang Y, Wang Y, Fang Y, Li C, Cao Y, Xiang H, Yin Z, Zhang D, Wei Z, He Y
Autophagy · 2026 Jun · PMID 42290145 · Publisher ↗
Obesity is recognized as a key contributor to the impaired endometrial receptivity that results in infertility; however, the molecular mechanisms underlying endometrial dysfunction remain incompletely understood. In this...
Obesity is recognized as a key contributor to the impaired endometrial receptivity that results in infertility; however, the molecular mechanisms underlying endometrial dysfunction remain incompletely understood. In this study, proteomic and ubiquitination analyses of secretory-phase endometrial tissue revealed a significant upregulation of SNCA/synuclein alpha and dysregulation of macroautophagy/autophagy in women with obesity. SNCA is best known for its role in neurodegenerative protein aggregation disorders. Proteomic and ubiquitination analysis of secretory-phase endometrial tissue revealed a significant upregulation of SNCA and dysregulation of autophagy in women with obesity. This study aimed to elucidate the role and mechanistic basis of SNCA and autophagy in obesity-associated endometrial receptivity defects. We demonstrated that elevated SNCA expression in endometrium and endometrial stromal cells (ESCs) correlated with impaired autophagy and disrupted decidualization in and . Mechanistically, SNCA directly interacted with the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box containing protein 1) in ESCs, thereby disrupting the association between STUB1 and phosphorylated TFEB (transcription factor EB; p-TFEB). This interaction attenuated p‑TFEB degradation, leading to suppressed autophagic flux and ultimately compromised decidualization of ESCs. Conversely, knockout alleviated obesity-induced endometrial impairments in mice. Moreover, STUB1 overexpression rescued decidualization and autophagy defects. Notably, metformin intervention restored autophagic activity and endometrial receptivity in obese mice by downregulation of SNCA independent of its autophagy-modulating effects. Together, these findings uncovered a novel pathogenic mechanism in which obesity-driven SNCA overexpression impairs endometrial receptivity by inhibiting STUB1-TFEB-mediated autophagy, positioning the SNCA-STUB1-TFEB axis as a promising therapeutic target for obesity-related endometrial infertility.: BECN1: beclin 1; CCK-8: Cell Counting Kit-8; CQ: chloroquine; DEPs: differentially expressed proteins; DIO: diet-induced obese; ESCs: endometrial stromal cells; FBS: fetal bovine serum; GD7: gestational day 7; GSEA: Gene Set Enrichment Analysis; HFD: high-fat diet; HOXA10: homeobox A10; IGFBP1: insulin like growth factor binding protein 1; IPGTT: intraperitoneal glucose tolerance test; LIF: LIF interleukin 6 family cytokine; PBS: phosphate-buffered saline; PRL: prolactin; Rapa: rapamycin; SNCA/synuclein alpha; SQSTM1/p62: sequestosome 1; STUB1: STIP1 homology and U-box containing protein 1; TC: total cholesterol; TEM: transmission electron microscopy; TFEB: transcription factor EB; UPS: ubiquitin-proteasome system; WOI: window of implantation.
Melatonin alleviates rheumatoid arthritis via elimination of damaged mitochondria.
Wang B, Wu Y, Li G … +6 more , Che Z, Sun Q, Wang C, Gao Y, Li L, Cai M
Autophagy · 2026 Jun · PMID 42290138 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease primarily characterized by symmetrical synovial inflammation, leading to joint swelling, pain, and progressive cartilage and bone destruction. Unfortuna...
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease primarily characterized by symmetrical synovial inflammation, leading to joint swelling, pain, and progressive cartilage and bone destruction. Unfortunately, the clinical treatment of RA still faces numerous challenges. Although melatonin (MT), the circadian rhythm hormone, is known to relieve the pathological process of RA, the underlying mechanism remains poorly understood. Herein, we assess the impacts of MT on collagen or K/BxN serum-induced arthritis (two well-established models of RA) and confirm its excellent therapeutic effect. Mechanistically, MT activates MTNR1A (melatonin receptor 1A) to promote mitophagy for the elimination of reactive oxygen (ROS) and leaked mitochondrial DNA triggered by damaged mitochondria, which in turn limits NLRP3 (NLR family pyrin domain containing 3) inflammasome activation and pro-inflammatory cytokine release. Mice with deletion of the autophagy-related gene in myeloid cells ( ) barely display any benefits of MT in K/BxN serum-induced arthritis. Our results indicate that mitophagy promoted by MT is essential to deactivate NLRP3 inflammasome and alleviate the development of arthritis, which provides a candidate for the treatment of RA. 3-MA: 3-methyladenine; ACP5/TRAP: acid phosphatase 5, tartrate resistant; ANOVA: analysis of variance; ATG5: autophagy releated 5; ATP: adenosine triphosphate; BMD: bone mineral density; BMDMs: bone marrow derived macrophages; BV:TV: bone volume to tissue volume; CASP1: caspase 1; CYCS: cytochrome c; DNM1L/DRP1: dynamin 1 like; EtBr: ethidium bromide; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GSDMD: gasdermin D; IL1B/IL-1β: interleukin 1 beta; IL18: interleukin 18; LPS: lipopolysaccharide; MT: melatonin; MTNR1A: melatonin receptor 1A; MTNR1B: melatonin receptor type 1B; MFF: mitochondrial fission factor; mtROS: mitochondrial reactive oxygen species; mt-DNA: mitochondrial DNA; NAC: N-acetylcysteine; NT-GSDMD: N-terminal gasdermin D; NLRP3: NLR family pyrin domain containing 3; Ox-mtDNA: oxidized mitochondrial DNA; PINK1: PTEN induced kinase 1; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; PRKN: parkin RBR E3 ubiquitin protein ligase; PYCARD/ASC: PYD and CARD domain containing; RA: rheumatoid arthritis; ROS: reactive oxygen; SD: standard deviation; SQSTM1/p62: sequestosome 1; Tb.N: trabecular number; Tb.Th: trabecular thickness; TNF/TNF-α: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1.
MoCox6 is a potential fungicide target regulating mitophagy in .
Wu MH, Zhu XM, Klionsky DJ … +2 more , Lin FC, Liu XH
Autophagy · 2026 Jun · PMID 42287089 · Publisher ↗
Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in remains poorly understood. In our recent study, we found that upon oute...
Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in 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 Lys144 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.: ATG, autophagy related; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; MoCox6, cytochrome oxidase subunit 6; MoSirt5, sirtuin 5 desuccinylase.
E-cigarette aerosols induce the hydrolysis of lysosomal glycerophospholipids through PLA2G4A activation initiated by nicotine binding to CHRNA3/α3 nAChR in airway epithelial cells.
Yu Y, Xu S, Yang L … +9 more , Shu S, Zhou H, Hua Z, Wang L, Zhu Y, Shi A, Xia R, Chen C, Wang SL
Autophagy · 2026 Jun · PMID 42287088 · Publisher ↗
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 demons...
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 Ca overload. Genetic or pharmaceutical inhibition of CHRNA3 reduced intracellular Ca 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.: AACOCF3: arachidonyl trifluoromethyl ketone; AB-PAS: Alcian Blue Periodic Acid Schiff; ANXA5: annexin V; AOP: adverse outcome pathway; ATG: autophagy related; BECN1: beclin 1; CASP3: caspase 3; CASP7: caspase 7; CASP9: caspase 9; CQ: chloroquine; CHRNA/nAChR: cholinergic receptor nicotinic alpha subunit; CTSD: cathepsin D; DHE: dihydroethidium; DMSO: dimethyl sulfoxide; E-cigarette: electronic cigarette; ENGASE/NAG: endo-beta-N-acetylglucosaminidase; FBS: fetal bovine serum; GA: geldanamycin; GSH: glutathione; HBE: human bronchial epithelial; HEX: hexamethonium; LAMP: lysosome associated membrane protein; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LGALS3: galectin 3; LBD: ligand-binding domain; LMP: lysosomal membrane permeabilization; LPC: lysophosphatidylcholine; LPE: lysophosphatidylethanolamine; MAP1LC3/LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehyde; MIE: molecular initiating event; MTBE: methyl tert-butyl ether; MTOR: mechanistic target of rapamycin kinase; mtROS: mitochondrial reactive oxygen species; NBR1: NBR1 autophagy cargo receptor; PBS: phosphate-buffered saline; PC: diacyl glycerophosphatidylcholine; PE: diacyl glycerophosphatidylethanolamine; Penh: pulmonary resistance; PG: propylene glycol; PLA2G4A/cPLA2: phospholipase A2 group IVA; PLA2G4E: phospholipase A2 group IVE; ROS: reactive oxygen species; siRNA: small interfering RNA; SOD: superoxide dismutase; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VG: vegetable glycerin.
STING1 senses mitochondrial damage to promote mitophagy.
Huang ZB, Lin JY, Cheng LJ … +3 more , Tan HWS, Shen HM, Lu G
Autophagy · 2026 Jun · PMID 42287086 · Publisher ↗
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 autopha...
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.: 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.
H3K18la- driven neutrophil secretory autophagy promotes pulmonary endothelial dysfunction in sepsis-induced lung injury.
Li Y, Li R, Zhu D … +7 more , Tian R, Chen Y, Wang X, Li L, Pan T, Tan R, Qu H
Autophagy · 2026 Jun · PMID 42283498 · Publisher ↗
Endothelial dysfunction is a critical determinant of sepsis-associated organ injury, often driven by its interaction with overactivated immune cells. Neutrophils, the dominant early responders in sepsis, contribute to en...
Endothelial dysfunction is a critical determinant of sepsis-associated organ injury, often driven by its interaction with overactivated immune cells. Neutrophils, the dominant early responders in sepsis, contribute to endothelial barrier disruption, yet the underlying metabolic and epigenetic mechanisms remain poorly understood. Here, we observed elevated intracellular lactate levels in neutrophils from septic patients which correlated with organ dysfunction and systemic inflammatory markers. Mechanistically, lactate-induced histone H3K18 lactylation (H3K18la) enhanced (autophagy related 7) transcription, initiating a non-degradative, secretory autophagy program. This facilitated the extracellular release of IL1B/IL-1B (interleukin 1 beta), a key driver of endothelial dysfunction. Interference of lactate production, ATG7 expression or IL1B signaling alleviated endothelial dysfunction . , myeloid-specific deletion of the lactylation writer EP300/p300 (EP300 lysine acetyltransferase) mitigated pulmonary endothelial dysfunction and lung injury. Additionally, the stress-responsive transcription factor ATF4/CREB-2 (activating transcription factor 4) was found to directly interact with both EP300 and H3K18la, amplifying H3K18la-driven transcription. Our findings uncover a metabolically driven, epigenetically regulated secretory autophagy pathway in neutrophils that mediates endothelial dysfunction. Our study provides mechanistic insights into neutrophil-endothelial crosstalk in sepsis and identifies EP300, ATG7, and IL1B as potential therapeutic targets for sepsis. ALI: acute lung injury; ANOVA: analysis of variance; ATF4/CREB-2: activating transcription factor 4; ATG7/GSA7: autophagy related 7; ATP: adenosine triphosphate; BafA1: bafilomycin A; BMDN: bone marrow-derived neutrophil; C-CASP1: cleaved-caspase 1; CDH5/CD144: cadherin 5; CRP/PTX1: C-reactive protein; CST3: cystatin C; CXCL8/IL-8: C-X-C motif chemokine ligand 8; DAPI: 4',6-diamidino-2-phenylindole; DEG: differentially expressed gene; dHL-60: dimethyl sulfoxide-differentiated HL-60 cell; DMSO: dimethyl sulfoxide; ELISA: enzyme-linked immunosorbent assay; EP300/p300: EP300 lysine acetyltransferase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; GSDMD-N: gasdermin D N-terminal; H&E: hematoxylin and eosin; H3K18la: histone H3K18 lactylation; HRP: horseradish peroxidase; ICU: intensive care unit; IHC: immunohistochemistry; IL1B/IL-1B: interleukin 1 beta; IL1R1/CD121A: interleukin 1 receptor type 1; IL6/IL-6: interleukin 6; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAMP1/CD107a: lysosome associated membrane protein 1; LDHA: lactate dehydrogenase A; LPS: lipopolysaccharide; 3-MA: 3-methyladenine; NLRP3/NALP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PCT: procalcitonin; PMN: peripheral neutrophils; Rapa: rapamycin; RNA-seq: RNA-sequencing; SERPINE1/PAI1: serpin family E member 1; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; SOFA: Sequential Organ Failure Assessment; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TNF/TNF-alpha: tumor necrosis factor; panKla: pan-histone lactylation; VCAM1/CD106: vascular cell adhesion molecule 1.
Cell stress and death liberate the autophagy-inhibitory tissue stress hormone DBI/ACBP into the circulation.
Rong Y, Lambertucci F, Yang Y … +4 more , Dong Y, Maiuri MC, Martins I, Kroemer G
Autophagy · 2026 Jun · PMID 42283134 · Publisher ↗
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...
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.
PFN1 inhibits lytic replication of Kaposi sarcoma-associated herpesvirus through SQSTM1/p62-mediated selective autophagy targeting the KSHV helicase.
Sun X, Dong J, Liang X … +6 more , Peng J, Chen Y, Yin R, Tan T, Bai L, Lan K
Autophagy · 2026 Jun · PMID 42260986 · Publisher ↗
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 rep...
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. ALS: amyotrophic lateral sclerosis; Baf A1: bafilomycin A; co-IP: co-immunoprecipitation; KSHV: Kaposi sarcoma-associated herpes virus; LIR: LC3-interacting region; PFN1: profilin 1; SQSTM1/p62: sequestosome 1; TRIM37: tripartite motif containing 37; UBA: ubiquitin-associated domain.
Porcine reproductive and respiratory syndrome virus hijacks the non-canonical enzymatic function of PHGDH to arrest autophagic flux for viral replication.
Yu Z, Zhou Q, Gao P … +6 more , Zhang Y, Ge X, Han J, Guo X, Zhou L, Yang H
Autophagy · 2026 Jun · PMID 42260976 · Publisher ↗
Viruses frequently hijack host metabolic enzymes to fuel replication. However, the mechanisms underlying this hijacking and utilization of metabolic enzymes remain poorly understood. In this study, we report a sophistica...
Viruses frequently hijack host metabolic enzymes to fuel replication. However, the mechanisms underlying this hijacking and utilization of metabolic enzymes remain poorly understood. In this study, we report a sophisticated mechanism by which porcine reproductive and respiratory syndrome virus (PRRSV) exploits a non-canonical enzymatic function of PHGDH (phosphoglycerate dehydrogenase) to modulate macroautophagy/autophagy. We demonstrate that PRRSV infection recruits the transcription factor ZNF143 (zinc finger protein 143) to transcriptionally repress PHGDH expression. Importantly, the antiviral restriction activity of PHGDH is entirely uncoupled from its canonical enzymatic role in serine biosynthesis. Mechanistically, PHGDH depletion triggers the initiation of autophagy via the AMP-activated protein kinase (AMPK)-ULK1 (unc-51 like autophagy activating kinase 1) signaling axis; however, it paradoxically arrests autophagic flux at the autophagosome-lysosome fusion stage. PHGDH is identified as a critical scaffold that facilitates the assembly of the autophagic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex; its downregulation disrupts the interaction between STX17 (syntaxin 17) and SNAP29 (synaptosome associated protein 29), thereby blocking autophagosome-lysosome fusion. This induction of incomplete autophagy creates a favorable cytosolic niche for viral replication. Furthermore, the antiviral effect of PHGDH is also observed in two other swine pathogens, porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV). Collectively, these findings revealed that viruses weaponized the moonlighting function of a metabolic enzyme to dismantle autophagic flux, highlighting PHGDH as a broad-spectrum antiviral target that bridged metabolism and membrane trafficking. AMPK: AMP-activated protein kinase; BECN1: beclin 1; CQ: chloroquine; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; PEDV: porcine epidemic diarrhea virus; PHGDH: phosphoglycerate dehydrogenase; PRV: pseudorabies virus; PRRSV: porcine reproductive and respiratory syndrome virus; SGOC: serine-glycine-one-carbon; siRNA: small interfering RNA; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SSP: serine synthesis pathway; STX17: syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; ZNF143: zinc finger protein 143.
Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.
Zhang Y, Sun J, Cui Y
Autophagy · 2026 Jun · PMID 42237481 · Publisher ↗
Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) ab...
Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) abnormalities are prominent features of Alzheimer's disease (AD), whether reticulophagy directly contributes to amyloid precursor protein (APP) turnover has remained unclear. We identify FAM134B/RETREG1 as a specific receptor that recognizes ER-localized APP and promotes its lysosomal degradation through LC3-dependent reticulophagy. In AD patient samples and 5XFAD mice, epigenetic repression of FAM134B limits TFEB/TFE3-dependent transcription, resulting in impaired ER turnover, APP accumulation, and exacerbated amyloid pathology. Restoration of wild-type, but not LIR-mutant, FAM134B rescues reticulophagy, reduces APP and Aβ accumulation, preserves neuronal integrity, and improves cognition in 5XFAD mice. These findings establish impaired reticulophagy as an upstream pathogenic mechanism in AD and highlight FAM134B-mediated ER turnover as a potential therapeutic strategy for limiting amyloidogenic APP accumulation.
Vacuolar sorting receptors regulates autophagic trafficking of pathogenic effectors in plant immunity.
Hu S, Zhu D, Gao Y … +2 more , Rojo E, Shen J
Autophagy · 2026 Jun · PMID 42237479 · Publisher ↗
Selective autophagy functions not only in nutrient recycling and stress adaptation but also in the degradation of pathogen-derived virulence effectors during effector‑triggered immunity (ETI). However, how vacuolar sorti...
Selective autophagy functions not only in nutrient recycling and stress adaptation but also in the degradation of pathogen-derived virulence effectors during effector‑triggered immunity (ETI). However, how vacuolar sorting receptors (VSRs) coordinate endomembrane trafficking and selective autophagy during ETI remained poorly understood. In a recent study, we identified four pathogen‑inducible VSRs (VSR1, VSR5, VSR6, VSR7) that play important roles in regulating vacuolar cargo sorting, tonoplast - plasma membrane fusion, and hypersensitive cell death during ETI. Importantly, upon pathogen invasion and immune activation, VSR1 dynamically relocalized from the prevacuolar compartment/multivesicular body (PVC/MVB) to ATG8-positive autophagosomes. Moreover, loss of VSR function impaired autophagic flux and disrupted degradation of bacterial effectors. These observations illustrated a model in which pathogen-responsive VSRs function as a trafficking hub, integrating secretory and effector-phagy to enable rapid and effective plant immunity during ETI.: VSRs, vacuolar sorting receptors; TGN, trans-Golgi network; PVC/MVB, prevacuolar compartment/multivesicular body; ETI, effector‑triggered immunity; ; PM, plasma membrane; NLR, nucleotide-binding leucine-rich repeat; HR, hypersensitive response; ECS, extracellular space; NPR1, nonexpressor of pathogenesis-related genes 1; AP, adaptor protein; PLCPs, pathogen-inducible papain-like cysteine proteases; ATG, autophagy-related; NBR1, neighbor of BRCA1 gene 1 protein; FLS2, FLAGELLIN-SENSING 2.
p62 cleavage: a species-specific twist in TNF signalling.
Troitskaya O, Nössing C, Ryan KM
Autophagy · 2026 Jun · PMID 42237459 · Publisher ↗
Macroautophagy (hereafter referred to as autophagy) plays a key role in maintaining cellular homeostasis and shaping response to stress and inflammation. We outline here that inflammatory cytokines trigger caspase-8-depe...
Macroautophagy (hereafter referred to as autophagy) plays a key role in maintaining cellular homeostasis and shaping response to stress and inflammation. We outline here that inflammatory cytokines trigger caspase-8-dependent cleavage of the autophagy adaptor protein p62/SQSTM1 at aspartic acid 329 generating a truncated form (tr-p62). Tr-p62 enhanced TNF-induced cell death by stabilizing the RIPK1-dependent complex-IIb and amplifying caspase-8 activation, while having no detectable effect on necroptosis. Blocking autophagy leads to tr-p62 accumulation and increased TNF-induced cell death, while non-cleavable p62 reduced autophagic responses and TNF sensitivity. Interestingly, mice naturally lack the caspase-8 cleavage site in p62 and restoring a cleavable version of p62 sensitized mouse cells to TNF-induced cell death. In addition, mice with cleavable p62 showed heightened sensitivity to TNF-induced toxic shock and chemical colitis . These findings identify p62 cleavage as a key regulator linking autophagy to TNF-driven inflammatory cell death and highlight an important species-specific difference that may influence the interpretation of inflammatory disease models. DSS: dextran sulfate sodium; FADD: Fas-associated death domain protein; LC3: microtubule-associated protein 1A/1B-light chain 3; PROTAC: proteolysis-targeting chimera; RIPK1: receptor-interacting serine/threonine-protein kinase 1; SMAC: second mitochondria-derived activator of caspases; TNF: tumour necrosis factor; TRAIL: TNF-related apoptosis-inducing ligand.
WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway.
Liu D, Cheng Y, Huang C … +13 more , Xie K, Jie J, Zhang Q, Lan L, Chen P, Xie J, Wang H, Ren L, Li H, Geng L, Gong S, Zhu Y, Cheng Y
Autophagy · 2026 Jun · PMID 42233622 · Publisher ↗
WNT2B is canonically characterized as a secreted WNT-family ligand, which is transported to the extracellular space via the endoplasmic reticulum (ER)-Golgi pathway and binds to cell surface FZDs (frizzled class receptor...
WNT2B is canonically characterized as a secreted WNT-family ligand, which is transported to the extracellular space via the endoplasmic reticulum (ER)-Golgi pathway and binds to cell surface FZDs (frizzled class receptors) to trigger downstream signaling cascades. Here, we identify a previously unrecognized non-secretory intracellular function of WNT2B in impairing endosomal trafficking to inhibit macroautophagy/autophagy, as well as a non-canonical LC3B-II-dependent autophagic secretion mechanism for WNT2B. Specifically, the non-secretory intracellular pool of WNT2B via its conserved middle domain (MD) binds to the spectrin repeat domain (SRD) of WASHC5, competitively displacing WASHC1 and thereby disrupting WASH complex assembly and inhibiting WASHC1-mediated actin polymerization on early endosomes. This disruption impairs endosomal cargo trafficking, including the core autophagy protein ATG9A, leading to defective autophagy initiation and subsequent accumulation of pro-inflammatory and pro-fibrotic factors in fibroblasts. We validated this mechanism in vivo using a TNBS-induced mouse model of chronic colitis. Fibroblast-specific deletion restores autophagy, reduces pro-inflammatory cytokine secretion, and ameliorates intestinal fibrosis. Consistently, in Crohn disease (CD) patient tissues, elevated WNT2B in fibrotic regions negatively correlates with autophagy activity, and positively correlates with pro-fibrotic phenotypes, and clinical disease severity. Moreover, we identify a novel LC3B-II-dependent autophagic secretion pathway for WNT2B, which is distinct from the conventional ER-to-Golgi-dependent protein secretion. Collectively, our study delineates a novel non-canonical WNT2B-WASH complex-ATG9A regulatory axis through which WNT2B impairs endosomal trafficking and disrupts autophagy, ultimately amplifying inflammation and fibrosis. This study suggests that WNT2B may serve as a promising therapeutic target for CD and autophagy-associated fibrotic disorders.: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTA2: actin alpha 2, smooth muscle; ARPC2: actin related protein 2/3 complex subunit 2; ATG: autophagy related; CCN3: cellular communication network factor 3; CD: Crohn disease; CK666: 2-fluoro-N-[2-(2-methyl-1H-indol-3-yl)ethyl]benzamide; COL1A1: collagen type I alpha 1 chain; Co-IP: co-immunoprecipitation; CTNNB1: catenin beta 1; DBcAMP: dibutyryl cyclic adenosine monophosphate; DPT: dermatopontin; EEA1: early endosome antigen 1; EGFR: epidermal growth factor receptor; ELISA: enzyme-linked immunosorbent assay; ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; EV: extracellular vesicle; FRAP: fluorescence recovery after photobleaching; FL: full length; FZD: frizzled class receptor; GST: glutathione S-transferase; HIF: human intestinal fibroblast; HMGB1: high mobility group box 1; IKBKB: inhibitor of nuclear factor kappa B kinase subunit beta; IL6: interleukin 6; LDELS: LC3-dependent EV loading and secretion; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: middle domain; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; MVB: multivesicular body; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; PDCD6IP: programmed cell death 6 interacting protein; PLA: proximity ligation assay; RELA/p65: RELA proto-oncogene, NF-kB subunit; SAFB: scaffold attachment factor B; SES-CD: Simple Endoscopic Score for Crohn disease; SIM: super-resolution structured illumination microscopy; SMAD3: SMAD family member 3; SQSTM1/p62: sequestosome 1; SRD: spectrin repeat domain; TEM: transmission electron microscopy; TFRC: transferrin receptor; TGFB1: transforming growth factor beta 1; TGOLN2: trans-golgi network protein 2; TNBS: 2,4,6-trinitrobenzenesulfonic acid; TNF: tumor necrosis factor; VCA: Verprolin homology, Central and Acidic; WASHC: WASH complex subunit; WLS: Wnt ligand secretion mediator; WCL: whole cell lysates; WNT: Wnt family member; WT, wild type.
The autophagy-inhibitory tissue hormone DBI/ACBP contributes to the pathogenesis of multiple organ dysfunction syndrome in septic shock.
Lambertucci F, Maiuri MC, Martins I … +1 more , Kroemer G
Autophagy · 2026 Jun · PMID 42226409 · Publisher ↗
Systemic microbial infection leading to septic shock with multiple organ dysfunction syndrome (MODS) is a major cause of mortality and represents a substantial unmet medical need. We recently observed that, compared with...
Systemic microbial infection leading to septic shock with multiple organ dysfunction syndrome (MODS) is a major cause of mortality and represents a substantial unmet medical need. We recently observed that, compared with uninfected controls, patients with septic shock exhibit significantly elevated circulating concentrations of the tissue hormone acyl-CoA binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, a potent inhibitor of autophagy. Increased plasma DBI/ACBP levels correlated with disease severity and poor clinical outcome. Similarly, DBI/ACBP concentrations were elevated in three distinct mouse models of septic shock induced by (i) bacterial lipopolysaccharide injection, (ii) inoculation with monomicrobial or (iii) polymicrobial sepsis following cecal ligation and puncture. In all three models, neutralization of DBI/ACBP using specific monoclonal antibodies significantly reduced mortality. Comprehensive behavioral, cardiac, pulmonary, hepatic, renal and splenic phenotyping further demonstrated that DBI/ACBP neutralization alleviated all hallmarks of MODS, including impaired thermoregulation, lethargy and organ failure affecting the heart, lungs, liver and kidneys. Multi-omics analyses, including bulk transcriptomics, metabolomics and high-dimensional immunophenotyping, revealed that DBI/ACBP neutralization attenuated sepsis-associated alterations in gene expression, metabolism and myeloid cell infiltration across major organs. Mechanistically, DBI/ACBP inhibition enhanced organ resistance to lipopolysaccharide-induced sterile inflammation while simultaneously promoting bacterial clearance by macrophages and granulocytes both and in models of monomicrobial and polymicrobial sepsis. Collectively, these findings identify DBI/ACBP as a pathogenic mediator of sepsis, consistent with its previously described anti-autophagic, immunosuppressive, pro-inflammatory and pro-senescent properties.
AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer's disease.
Dong Y, Xiao X, Zhuang XX … +5 more , Wu W, Fang EF, Yang G, Niu Z, Lu JH
Autophagy · 2026 May · PMID 42218670 · Publisher ↗
Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising th...
Current Alzheimer's disease therapies offer limited efficacy and are often accompanied by significant side effects, underscoring the urgent need for new treatment strategies. Enhancing autophagy represents a promising therapeutic approach, yet most known autophagy inducers act through the mTOR-dependent pathway, which broadly affects cellular metabolism and proliferation, and their clinical potential is further limited by poor blood-brain barrier (BBB) penetration. To address these twin challenges, an artificial intelligence (AI)-driven platform named DeepDrugDiscovery was developed, shifting the focus from traditional structure-based screening toward a mechanism-centric strategy for identifying mTOR-independent autophagy enhancers with brain penetrability. The platform screened over one million molecules and identified two lead compounds, Ombuin and 2-Hydroxycinnamic acid, which were experimentally shown to clear pathogenic tau and amyloid-β aggregates and restore memory function in both worm and mouse models of Alzheimer's disease. Notably, Ombuin exhibited robust brain exposure, confirming accurate BBB prediction. Released as an open-source resource, DeepDrugDiscovery demonstrates a scalable, AI-powered pipeline for discovering mechanism-based therapeutics.
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