CDK4/MERCs/PINK1 Axis Drives PFOA/HFPO‐TA‐Induced Cardiac Senescence via Mitophagy Defect and cGAS‐STING Activation: In Vitro Amelioration by Cycloastragenol

ABSTRACT

Per‐ and polyfluoroalkyl substances (PFAS) are ubiquitous persistent environmental pollutants with high bioaccumulation potential and widespread human exposure risks in contaminated water, soil, and biota. 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‐TA). Exposure to either PFOA or HFPO‑TA caused cardiac structural and functional damage, mitochondrial morphological abnormalities, and increased cardiac senescence, with HFPO‐TA eliciting greater cardiotoxicity. Mechanistically, PFOA and HFPO‐TA suppress CDK4 expression, destabilize mitochondria‐endoplasmic reticulum contacts (MERCs), and impair PINK1/Parkin‐mediated mitophagy. This defective mitophagy promotes mitochondrial DNA leakage and subsequent activation of the cGAS‐STING pathway, ultimately driving cardiac senescence. Notably, cycloastragenol (CAG) effectively reverses CDK4 downregulation, restores MERCs stability, and attenuates PFOA/HFPO‐TA‐induced cardiac senescence in vitro. Collectively, this study uncovers a CDK4/MERCs/PINK1 axis mediating PFOA/HFPO‐TA‐induced myocardial toxicity and identifies CAG as a promising natural product for mitigating environmental pollutant‐induced cardiac senescence, offering insights for PFAS health risk assessment and intervention strategies.