Academic Journal
Attenuated FTO induces necroptosis of alveolar epithelium via the m6A/CYP1B1/ROS/MLKL axis to promote the aggravation of pulmonary emphysema.
| Τίτλος: | Attenuated FTO induces necroptosis of alveolar epithelium via the m6A/CYP1B1/ROS/MLKL axis to promote the aggravation of pulmonary emphysema. |
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| Συγγραφείς: | Wu M; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Wang W; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Chen Z; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Yang Y; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China., Yan J; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China., Cui Y; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Huang P; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Zhang F; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Tu W; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Chen W; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China., Sun R; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China., Zhou Y; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China. Electronic address: zhouyumin410@126.com., Zhu L; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China. Electronic address: zhuleqing1@163.com., Ran P; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, 510005, China; Guangzhou National Laboratory, Guangzhou International BioIsland, No.9 XingDaoHuanBei Road, Guangzhou, Guangdong, 510005, China. Electronic address: pxran@gzhmu.edu.cn. |
| Πηγή: | Redox biology [Redox Biol] 2026 Sep; Vol. 95, pp. 104237. Date of Electronic Publication: 2026 May 27. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| Ιατρικοί όροι (MeSH): | Alpha-Ketoglutarate-Dependent Dioxygenase FTO*/metabolism , Alpha-Ketoglutarate-Dependent Dioxygenase FTO*/genetics , Pulmonary Emphysema*/metabolism , Pulmonary Emphysema*/pathology , Pulmonary Emphysema*/etiology , Pulmonary Emphysema*/genetics , Alveolar Epithelial Cells*/metabolism , Alveolar Epithelial Cells*/pathology , Necroptosis*, Reactive Oxygen Species/metabolism ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology ; Animals ; Humans ; Mice ; Disease Models, Animal ; Male ; RNA Methylation ; Oxidative Stress ; Signal Transduction |
| Περίληψη: | Emphysema is a major phenotype of chronic obstructive pulmonary disease (COPD) and reflects sustained oxidative injury and defective alveolar repair in the distal lung. While cigarette smoke is the dominant environmental trigger, endogenous epithelial programs that restrain reactive oxygen species (ROS) and preserve alveolar integrity remain poorly defined in the adult lung parenchyma. Here we identify that fat mass and obesity-associated protein (FTO) as a redox-responsive regulator in the alveolar epithelium. FTO is predominantly expressed in alveolar type II (AT2) epithelial cells and is markedly reduced in both the epithelium of human COPD patients and the lungs of cigarette smoke-exposed mice. This reduction correlated with worse pulmonary function and was inversely associated with cumulative smoking burden in human. Global attenuation of FTO expression resulted in spontaneous emphysema and impaired lung mechanics in mice. Mechanistically, FTO deficiency promotes cytochrome P450 1B1 (CYP1B1) expression via increased m6A modification and mRNA stabilization, thereby enhancing ROS accumulation and activating the necroptotic effector mixed lineage kinase domain-like protein (MLKL). Genetic silencing of CYP1B1 or antioxidant treatment with N-acetylcysteine (NAC) attenuated ROS and necroptosis. Moreover, conditional deletion of FTO in AT2 cells exacerbated oxidative stress, phosphorylated-MLKL/MLKL levels, and emphysematous injury in mice, indicating spontaneous emphysema driven by necroptosis-effects that were further aggravated in a chronic cigarette smoke-induced COPD model. NAC treatment effectively alleviated the COPD-related deterioration caused by FTO deficiency in AT2 cells. Together, these findings define an alveolar epithelial FTO-m6A-CYP1B1-ROS-MLKL axis that links redox dysregulation to necroptotic cell death and alveolar destruction, and they nominate FTO as a tractable node for redox-targeted intervention in COPD-related emphysema. (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
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| Contributed Indexing: | Keywords: Alveolar epithelium; COPD; Emphysema; FTO; Necroptosis; Oxidative stress |
| Substance Nomenclature: | EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO) 0 (Reactive Oxygen Species) EC 1.14.11.33 (FTO protein, human) EC 1.14.11.- (FTO protein, mouse) |
| Entry Date(s): | Date Created: 20260602 Date Completed: 20260729 Latest Revision: 20260813 |
| Update Code: | 20260813 |
| PubMed Central ID: | PMC13251485 |
| DOI: | 10.1016/j.redox.2026.104237 |
| PMID: | 42229232 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2213-2317 |
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| DOI: | 10.1016/j.redox.2026.104237 |