Autophagy最新文献

{"title":"TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.","authors":"Jiong Yan, Xin Chen, Swati Choksi, Zheng-Gang Liu","doi":"10.1080/15548627.2025.2483441","DOIUrl":"10.1080/15548627.2025.2483441","url":null,"abstract":"<p><p>Selective clearance of damaged mitochondria through mitophagy is crucial for the maintenance of mitochondrial homeostasis. While mitophagy can be activated by various mitochondrial toxins, the physiologically relevant signal that triggers mitophagy is less studied. TGFB/TGFβ signaling has been linked to autophagic induction, but its specific role in mitophagy is not well understood. Here, we discovered a novel mitophagy induction paradigm stimulated by TGFB1. The mitophagic response is exclusively mediated by SMAD2, SMAD3, and SMAD4 underlying the TGFB receptor signaling. The transcriptional regulation activates genes involved in the canonical autophagic pathway which is required for the TGFB1-induced mitophagy. Moreover, TGFB1 signaling promotes mitophagic flux by upregulating PLSCR3 that externalizes cardiolipin in conjunction with the MAP1LC3/LC3/GABARAPs-interacting receptor proteins (BNIP3L/NIX, BNIP3, and FUNDC1)-dependent mechanism. Overall, our study characterized the essential components engaged in the TGFB1-induced mitophagy and demonstrated that TGFB is an important signal that induces mitophagy.<b>Abbreviations</b> ATG5: autophagy related 5; ATG8: mammalian homolog of yeast Atg8; ATG9A: autophagy related 9A; ATG13: autophagy related 13; ATG101: autophagy related 101; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Cardiolipin: 1,3-bis(<i>sn</i>-3'-phosphatidyl)-<i>sn</i>-glycerol; CERS1: ceramide synthase 1; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor-associated protein like 1; GABARAPL2: GABA type A receptor-associated protein like 2; GLS: glutaminase; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MitoIP: mitochondrial immunoprecipitation; MMP: mitochondrial membrane potential; NRBF2: nuclear receptor binding factor 2; OPTN: optineurin; PINK1: PTEN induced kinase 1; PLSCR3: phospholipid scramblase 3; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TGFB/TGFβ: transforming growth factor beta; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1791-1801"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATG9A controls all stages of autophagosome biogenesis.","authors":"Ruheena Javed, Muriel Mari, Einar Trosdal, Thabata Lopes Alberto Duque, Masroor Paddar, Lee Allers, Prithvi Akepati, Michal H Mudd, Fulvio Reggiori, Vojo Deretic","doi":"10.1080/15548627.2025.2494802","DOIUrl":"10.1080/15548627.2025.2494802","url":null,"abstract":"<p><p>Canonical autophagy is an intracellular pathway that degrades and recycles cellular components. A key step of this pathway is the formation of double-membraned organelles, known as autophagosomes, an emblematic feature of macroautophagy. For convenience, the formation of autophagosomes can be categorized into sequential steps, initiation (X), expansion (Y) and closure (Z). ATG9A is an integral membrane protein known for its role in the X and Y steps. whereby it organizes phagophore membrane assembly and its growth. Here, we report a previously unappreciated function of mammalian ATG9A in directing the last step Z. In particular, ATG9A partners with the key ESCRT-III component CHMP2A through IQGAP1 to facilitate autophagosome closure. Thus, ATG9A orchestrates all stages of autophagosome membrane biogenesis, from phagophore initiation to its closure. This makes ATG9A a unique ATG factor that works as a central hub in autophagosome biogenesis.<b>Abbreviation</b>: ATG9A autophagy related 9A; CCCP carbonyl cyanide m-chlorophenylhydrazone; Co-IP co-immunoprecipitation; ESCRT endosomal sorting complexes required for transport; EBSS Earle's balanced salt solution; ER endoplasmic reticulum; HCM high-content microscopy; HT HaloTag; LC-MS/MS liquid chromatography-tandem mass spectrometry; KO knockout; MPL membrane permeant ligand; MIL membrane impermeant ligand; Mtb Mycobacterium tuberculosis; SolVit sealing of organellar limiting membranes in vitro; TMR tetramethylrhodamine; WT wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1859-1861"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T16G12.6/IMPORTIN 13-mediated cytoplasm-to-nucleus transport of the THAP transcription factor LIN-15B controls autophagy and lysosome function in <i>C. elegans</i>.","authors":"Xiaoli Ma, Xiaomeng Gou, Hong Zhang","doi":"10.1080/15548627.2025.2482724","DOIUrl":"10.1080/15548627.2025.2482724","url":null,"abstract":"<p><p>Transcriptional regulation of genes involved in the macroautophagy/autophagy-lysosome pathway acts as an important mechanism for controlling autophagy activity. The factors that globally regulate autophagy activity at the transcriptional level during <i>C. elegans</i> development remain unknown. Here we showed that the THAP domain-containing transcription factor LIN-15B modulates autophagy activity during <i>C. elegans</i> development. Loss of function of <i>lin-15B</i> suppresses the autophagy defect caused by impaired autophagosome maturation and promotes lysosome biogenesis and function. LIN-15B maintains the repressed state of genes involved in the autophagy pathway. Accordingly, loss of function of <i>lin-15B</i> upregulates a plethora of genes involved in autophagosome formation and maturation as well as lysosome biogenesis and function. The cytoplasm-to-nucleus translocation of LIN-15B is mediated by the T16G12.6/IMPORTIN 13/IPO-13 receptor and modulated by nutrient status. Our study uncovers that LIN-15B integrates environmental cues into transcriptional control of a network of genes involved in autophagy in <i>C. elegans</i>.<b>Abbreviations:</b> ATG: autophagy related; DIC: differential interference contrast; EPG: ectopic PGL granules; ER: endoplasmic reticulum; FOXO: forkhead box O; GFP: green fluorescent protein; SQST-1: SeQueSTosome related 1; SynMuv: synthetic multivulva; IPO-13: importin 13; TFEB: transcription factor EB.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1779-1790"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coping with stress: the essential role of brain autophagy in emotional homeostasis.","authors":"Dimitra Dialynaki, Daniel J Klionsky","doi":"10.1080/15548627.2025.2520091","DOIUrl":"10.1080/15548627.2025.2520091","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":"21 8","pages":"1621-1622"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keeping your endosymbiont under control: the enigmatic plastid membrane ATG8ylation in Apicomplexa parasites.","authors":"Sébastien Besteiro","doi":"10.1080/15548627.2025.2483445","DOIUrl":"10.1080/15548627.2025.2483445","url":null,"abstract":"<p><p>ATG8ylation of membranes has been increasingly reported over the last few years, in various configurations and across different eukaryotic models. While the unconventional conjugation of ATG8 to the outermost membrane of the plastid in apicomplexan parasites was first observed over a decade ago, it is often overlooked in literature reviews focusing on the ATG8ylation of non-autophagosomal membranes. Here, I provide a brief overview of the current knowledge on plastid ATG8ylation in these parasites and discuss a possible parallel between the evolutionary origin of this plastid and other ATG8ylation processes, such as LC3-associated phagocytosis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1843-1847"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression.","authors":"Hyo Jeong Kim, Haeng-Jun Kim, Sun-Yong Kim, Jin Roh, Ju Hyun Yun, Chul-Ho Kim","doi":"10.1080/15548627.2025.2481661","DOIUrl":"10.1080/15548627.2025.2481661","url":null,"abstract":"<p><p>Tumorigenesis is closely linked to the ability of cancer cells to activate stress-adaptive mechanisms in response to various cellular stressors. Stress granules (SGs) play a crucial role in promoting cancer cell survival, invasion, and treatment resistance, and influence tumor immune escape by protecting essential mRNAs involved in cell metabolism, signaling, and stress responses. TBK1 (TANK binding kinase 1) functions in antiviral innate immunity, cell survival, and proliferation in both the tumor microenvironment and tumor cells. Here, we report that MUL1 loss results in the hyperactivation of TBK1 in both HNC cells and tissues. Mechanistically, under proteotoxic stress induced by proteasomal inhibition, HSP90 inhibition, or Ub⁺ stress, MUL1 promotes the degradation of active TBK1 through K48-linked ubiquitination at lysine 584. Furthermore, TBK1 facilitates autophagosome-lysosome fusion and phosphorylates SQSTM1, regulating selective macroautophagic/autophagic clearance in HNC cells. TBK1 is required for SG formation and cellular protection. Moreover, we found that MAP1LC3B is partially localized within SGs. TBK1 depletion enhances the sensitivity of HNC cells to cisplatin-induced cell death. GSK8612, a novel TBK1 inhibitor, significantly inhibits HNC tumorigenesis in xenografts. In summary, our study reveals that TBK1 facilitates the rapid removal of ubiquitinated proteins within the cell through protective autophagy under stress conditions and assists SG formation through the use of the autophagy machinery. These findings highlight the potential of TBK1 as a therapeutic target in HNC treatment.<b>Abbreviations</b>: ALP: autophagy-lysosomal pathway; AMBRA1: autophagy and beclin 1 regulator 1; BaF: bafilomycin A₁; CC: coiled-coil; CD274/PDL-1: CD274 molecule; CHX: cycloheximide; CQ: chloroquine; DNP: dinitrophenol; EGFR: epidermal growth factor receptor; ESCC: esophageal squamous cell carcinoma; G3BP1: G3BP stress granule assembly factor 1; HNC: head and neck cancer; HPV: human papillomavirus; IFN: interferon; IGFBP3: insulin like growth factor binding protein 3; IRF: interferon-regulatory factor 3; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; NPC: nasopharyngeal carcinoma; PABP: poly(A) binding protein; PI: proteasome inhibitor; PQC: protein quality control; PROTAC: proteolysis-targeting chimera; PURA/PURα: purine rich element binding protein A; RIGI: RNA sensor RIG-I; SD: standard deviation; SG: stress granule; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; UPS: ubiquitin-proteasome system; USP10: ubiquitin specific peptidase 10; VCP: valosin containing protein; VHL: von Hippel-Lindau tumor suppressor; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1744-1766"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the complexity of chaperone-mediated autophagy in aging: insights into sex-specific and cell-type-specific regulation.","authors":"Rongcan Luo","doi":"10.1080/15548627.2025.2489530","DOIUrl":"10.1080/15548627.2025.2489530","url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA) is a selective autophagic pathway that targets specific proteins for lysosomal degradation, playing a crucial role in maintaining cellular homeostasis. Recent research has highlighted the involvement of CMA in aging and age-related diseases, yet its regulation remains complex. The study by Khawaja et al. provides novel insights into the sex-specific and cell-type-specific regulation of CMA during aging. This commentary discusses the key findings of this study, their implications for autophagy and aging research, and potential future directions. Understanding these regulatory mechanisms is essential for developing targeted therapies to combat age-related diseases and promote healthy aging.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1848-1849"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TAX1BP1-dependent autophagic degradation of STING1 impairs anti-tumor immunity.","authors":"Ruoxi Zhang, Chunhua Yu, Herbert J Zeh, Guido Kroemer, Daniel J Klionsky, Daolin Tang, Rui Kang","doi":"10.1080/15548627.2025.2471736","DOIUrl":"10.1080/15548627.2025.2471736","url":null,"abstract":"<p><p>The activation of STING1 can lead to the production and secretion of cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library and identified tetrandrine, a bis-benzylisoquinoline alkaloid, as an immunological adjuvant that enhances antitumor immunity by preventing the autophagic degradation of the STING1 protein. This tetrandrine effect is independent of its known function as a calcium or potassium channel blocker. Instead, tetrandrine inhibits lysosomal function, impairing cathepsin maturation, and autophagic degradation. Proteomic analysis of lysosomes identified TAX1BP1 as a novel autophagic receptor for the proteolysis of STING1. TAX1BP1 recognizes STING1 through the physical interaction of its coiled-coil domain with the cyclic dinucleotide binding domain of STING1. Systematic mutation of lysine (K) residues revealed that K63-ubiquitination of STING1 at the K224 site ignites TAX1BP1-dependent STING1 degradation. Combined treatment with tetrandrine and STING1 agonists promotes antitumor immunity by converting \"cold\" pancreatic cancers into \"hot\" tumors. This process is associated with enhanced cytokine release and increased infiltration of cytotoxic T-cells into the tumor microenvironment. The antitumor immunity mediated by tetrandrine and STING1 agonists is limited by neutralizing antibodies to the type I interferon receptor or CD8⁺ T cells. Thus, these findings establish a potential immunotherapeutic strategy against pancreatic cancer by preventing the autophagic degradation of STING1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1802-1823"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTK6 drives HNRNPH1 phase separation to activate autophagy and suppress apoptosis in colorectal cancer.","authors":"Bingyuan Chen, Bowen Liu, Junnan Chen, Wenjing Li, Ning Ma, Jianquan Liu, Ruizhi Fan, Qihang Hu, Hu Song, Yixin Xu, Tao Jiang, Jun Song","doi":"10.1080/15548627.2025.2481001","DOIUrl":"10.1080/15548627.2025.2481001","url":null,"abstract":"<p><p>Macroautophagy/autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling, and has been reported to play a crucial role in colorectal cancer (CRC) pathogenesis and progression. Targeting autophagy may be a promising therapeutic strategy for CRC. However, the specific functions and potential mechanisms of autophagy in CRC remain unclear. In the present study, we discovered that PTK6 (protein tyrosine kinase 6) could activate autophagy and inhibit CRC apoptosis. PTK6 physically interacted with HNRNPH1 and mediated tyrosine phosphorylation at Y210 of HNRNPH1, which promoted the latter's liquid-liquid phase separation (LLPS). Furthermore, LLPS of HNRNPH1 formed biomolecular condensates and triggered splicing-switching of the <i>NBR1</i> exon 10 inclusion transcript, thereby activating autophagy and suppressing apoptosis of CRC. Additionally, PDO and CDX models indicated that tilfrinib, an inhibitor targeting PTK6, could inhibit CRC growth. Overall, our findings reveal the novel PTK6-HNRNPH1-NBR1 regulatory autophagy axis and provide a potential therapy target for CRC.<b>Abbreviation</b>: 1,6HD: 1,6-hexanediol, CQ: chloroquine, CRC: colorectal cancer, DFS: disease-free survival, FRAP: fluorescence recovery afterphotobleaching, GSEA: Gene Set Enrichment Analysis, GTEx: Genotype-Tissue Expression, HNRNPH1: heterogeneous nuclearribonucleoprotein H1, IDRs: intrinsically disordered regions, IHC: immunohistochemical, KEGG: Kyoto Encyclopedia of Genes and Genomes,LLPS: liquid-liquid phase separation, NBR1: NBR1 autophagy cargoreceptor, OS: overall survival, PDO: patient-derivedorganoid, PTK6: protein tyrosine kinase 6, PTMs: post-translationalmodifications, SE: skipped exon, TCGA: The Cancer Genome Atlas, TEM: transmission electron microscopy, TMA: tissue microarray, TyrKc: tyrosine kinase catalytic.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1680-1699"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics exacerbate ferroptosis via mitochondrial reactive oxygen species-mediated autophagy in chronic obstructive pulmonary disease.","authors":"Yuan Yuan Wei, Ting Ting Chen, Da Wei Zhang, Ying Zhang, Fang Li, Yi Chuan Ding, Ming Yu Wang, Ling Zhang, Ke Gong Chen, Guang He Fei","doi":"10.1080/15548627.2025.2481126","DOIUrl":"10.1080/15548627.2025.2481126","url":null,"abstract":"<p><p>Microplastics (MPs) induce mitochondrial dysfunction and iron accumulation, contributing to mitochondrial macroautophagy/autophagy and ferroptosis, which has increased susceptibility to the exacerbation of chronic obstructive pulmonary disease (COPD); however, the underlying mechanism remains unclear. We demonstrated that MPs intensified inflammation in COPD by enhancing autophagy-dependent ferroptosis (ADF) in vitro and in vivo. In the lung tissues of patients with COPD, the concentrations of MPs, especially polystyrene microplastics (PS-MPs), were significantly higher than that of the control group, as detected by pyrolysis gas chromatography mass spectrometry (Py-GCMS), with increased iron accumulation. The exposure to PS-MPs, 2 μm in size, resulted in their being deposited in the lungs of COPD model mice detected by optical in vivo imaging, and observed in bronchial epithelial cells traced by GFP-labeled PS-MPs. There were mitochondrial impairments accompanied by mitochondrial reactive oxygen species (mito-ROS) overproduction and significantly increased levels of lysosome biogenesis and acidification in pDHBE cells with PS-MP stimulation, triggering occurrence of ferritinophagy and enhancing ADF in COPD, which triggered acute exacerbation of COPD (AECOPD). Reestablishing autophagy-dependent ferroptosis via mitochondria-specific ROS scavenging or ferroptosis inhibition alleviated excessive inflammation and ameliorated AECOPD induced by PS-MPs. Collectively, our data initially revealed that MPs exacerbate ferroptosis via mito-ROS-mediated autophagy in COPD, which sheds light on further hazard assessments of MPs on human respiratory health and potential therapeutic agents for patients with COPD.<b>Abbreviations:</b> ADF: autophagy-dependent ferroptosis; AECOPD: acute exacerbation of chronic obstructive pulmonary disease; Cchord: static compliance; COPD: chronic obstructive pulmonary disease; CQ: chloroquine; CS: cigarette smoke; DEGs: differentially expressed genes; Fer-1: ferrostatin-1; FEV 0.1: forced expiratory volume in first 100 ms; FVC: forced vital capacity; GSH: glutathione; HE: hematoxylin and eosin; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; MDA: malondialdehyde; Mito-ROS: mitochondrial reactive oxygen species; MMA: methyl methacrylate; MMF: maximal mid-expiratory flow curve; MMP: mitochondrial membrane potential; MOI: multiplicity of infection; MPs: microplastics; MV: minute volume; PA: polyamide; PBS: phosphate-buffered saline; PC: polycarbonate; pDHBE: primary human bronchial epithelial cell from COPD patients; PET: polyethylene terephthalate; PIF: peak inspiratory flow; PLA: polylactic acid; pNHBE: primary normal human bronchial epithelial cell; PS-MPs: polystyrene microplastics; PVA: polyvinyl acetate; PVC: polyvinyl chloride; Py-GCMS: pyrolysis gas chromatography mass spectrometry; SEM: scanning electron microscopy; Te: expiratory times; Ti: inspiratory times; TNF/TNF-α: tumor necrosis factor.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1717-1743"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}