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The role of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in this process remains unclear, particularly regarding its expression and function. Atrial tissues were collected from patients with sinus rhythm or atrial fibrillation (AF) of varying durations. CFTR was downregulated in AF patients and negatively correlated with p16, p21, and p53. Myocardial aging models were established using D\u2010galactose (D\u2010gal) in both mice and neonatal mouse cardiomyocytes (CMs). In both animal and cellular models, D\u2010gal increased SA\u2010\u03b2\u2010gal positivity and senescence markers while decreasing CFTR. Overexpressing CFTR reduced D\u2010gal\u2010induced elevations in p16, p21, p53, and malondialdehyde (MDA), and restored superoxide dismutase (SOD), glutathione peroxidase (GSH\u2010Px), and catalase (CAT) activities. Mechanistically, CFTR alleviates mitochondrial oxidative stress damage by enhancing plasma membrane Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ATPase (PMCA) activity to reduce cytoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels. Furthermore, we identified USP45 as a direct binding partner of CFTR, which deubiquitinates CFTR by specifically targeting K48\u2010linked chains and the K688 residue. CFTR knockdown exacerbated D\u2010gal\u2010induced senescence and mitochondrial oxidative stress, which was rescued by USP45 overexpression. In conclusion, this study reveals a novel mechanism in which USP45\u2010mediated deubiquitination of CFTR mitigates cardiomyocyte senescence and mitochondrial oxidative stress, offering a targeted intervention against age\u2010related cardiovascular diseases.\n                  <\/jats:p>","DOI":"10.1111\/acel.70610","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T08:17:24Z","timestamp":1782202644000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Non\u2010Channel Function of\n                    <scp>CFTR<\/scp>\n                    : Attenuating Mitochondrial Oxidative Stress and Cardiomyocyte Senescence via Stabilization by\n                    <scp>USP45<\/scp>"],"prefix":"10.1111","volume":"25","author":[{"given":"Chun","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Hengyang Medical School The Changsha Central Affiliated Hospital, University of South China  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longtan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuewen","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine, The Changsha Central Affiliated Hospital, Hengyang Medical School University of South China  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Hengyang Medical School The Changsha Central Affiliated Hospital, University of South China  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Long","sequence":"additional","affiliation":[{"name":"Department of 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