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Although extensive studies have established the hepatotoxic potential of PFAS, much less is known regarding their cardiotoxicity and the underlying molecular mechanisms. Here, we investigated the cardiotoxic effects and molecular pathways of two representative PFAS, perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO\u2010TA). Exposure to either PFOA or HFPO\u2011TA caused cardiac structural and functional damage, mitochondrial morphological abnormalities, and increased cardiac senescence, with HFPO\u2010TA eliciting greater cardiotoxicity. Mechanistically, PFOA and HFPO\u2010TA suppress CDK4 expression, destabilize mitochondria\u2010endoplasmic reticulum contacts (MERCs), and impair PINK1\/Parkin\u2010mediated mitophagy. This defective mitophagy promotes mitochondrial DNA leakage and subsequent activation of the cGAS\u2010STING pathway, ultimately driving cardiac senescence. Notably, cycloastragenol (CAG) effectively reverses CDK4 downregulation, restores MERCs stability, and attenuates PFOA\/HFPO\u2010TA\u2010induced cardiac senescence in vitro. Collectively, this study uncovers a CDK4\/MERCs\/PINK1 axis mediating PFOA\/HFPO\u2010TA\u2010induced myocardial toxicity and identifies CAG as a promising natural product for mitigating environmental pollutant\u2010induced cardiac senescence, offering insights for PFAS health risk assessment and intervention strategies.<\/jats:p>","DOI":"10.1002\/advs.77280","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:43:57Z","timestamp":1787049837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDK4\/MERCs\/PINK1 Axis Drives PFOA\/HFPO\u2010TA\u2010Induced Cardiac Senescence via Mitophagy Defect and cGAS\u2010STING Activation: In Vitro Amelioration by Cycloastragenol"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9708-5518","authenticated-orcid":false,"given":"Nuo\u2010Wa","family":"Li","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Northeast Agricultural University  Harbin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010Ze","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Northeast Agricultural University  Harbin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Northeast Agricultural University  Harbin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian\u2010Tian","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Northeast Agricultural University  Harbin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8976-0513","authenticated-orcid":false,"given":"Kanwar 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