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Previous studies showed that club cells and club cell secretory proteins (CCSP) have anti\u2010inflammatory roles, which reduced in COPD. Klotho (KL) decreased in human COPD lung tissue. KL\u2010deficient mice showed aging phenotypes, such as obvious emphysema and premature senility at the early stage, which are characteristics of COPD. However, little is known about the relationship between KL, club cells, and COPD. We speculated lack of KL would aggravate club cell senescence, which contributes to COPD inflammation. We collected COPD lung tissue using single\u2010cell RNA sequencing (scRNA\u2010seq), revealing club cells heterogeneity and cellular senescence in COPD. In addition, KL and CCSP expressions were downregulated in cigarette smoke (CS)\u2010induced COPD mice, associated with increasing age\u2010related markers. After KL knockout, more ciliated cells appeared where club cells disappeared. Furthermore, KL deficiency aggravated club cell senescence and CSE\u2010induced pulmonary inflammation. To investigate the specific regulation mechanism, hnRNPA2\/B1 was recognised and identified it was the key molecule in KL\u2010regulated club cell senescence, and neddylation of club cell was a crucial factor contributing to hnRNPA2\/B1 downregulation. In\u00a0vitro, SA\u2010\u03b2\u2010gal staining suggested the aging phenotype was aggravated in hnRNPA2\/B1\u2010silenced groups, and hnRNPA2\/B1 over\u2010expressed achieved a rescue result. Thus, KL could regulate club cell senescence and differentiation. When CS stimulates the small airway epithelium, KL deficiency aggravates lung inflammation, club cell senescence and dysfunctional of ciliated cell. Targeting neddylation might be a promising strategy to reverse lung aging and club cell senescence. These results provide a mechanism about COPD\u2010linked lung inflammation.<\/jats:p>","DOI":"10.1111\/cpr.70000","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T02:23:27Z","timestamp":1739240607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Klotho Regulates Club Cell Senescence and Differentiation in Chronic Obstructive Pulmonary Disease"],"prefix":"10.1111","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5864-8809","authenticated-orcid":false,"given":"Min","family":"Li","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Jiangsu Province Hospital The First Affiliated Hospital of Nanjing Medical University  Nanjing China"},{"name":"Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital Jiangxi Medical College, Nanchang University  Nanchang China"},{"name":"China\u2010Japan Friendship Jiangxi Hospital National Regional Center for Respiratory Medicine  Nanchang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Jiangsu Province Hospital The First Affiliated Hospital of Nanjing Medical University  Nanjing China"},{"name":"Jiangsu Provincial Key Laboratory of Gerontology &amp; Geriatrics  Nanjing China"},{"name":"Jiangsu Provincial Innovation Center of Gerontology &amp; Geriatrics  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sibo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Respiratory, SuQian Branch of Jiangsu Province Hospital The First Affiliated Hospital of Nanjing Medical University  Suqian 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