Geniposide Attenuates Post-Myocardial Infarction Cardiac Remodeling via Parkin-Dependent Suppression of Hyperactivated Mitophagy

BACKGROUND: Cardiac remodeling Post-Myocardial Infarction (MI) drives heart failure. Geniposide (GP), a traditional Chinese medicine-derived compound, exhibits cardioprotective potential, yet its mechanisms remain unclear. This study explored the GP's role in post-MI remodeling via Parkin-dependent mitophagy. METHODS: Murine MI and cardiomyocyte Chronic Hypoxia (CH) models were established. MI mice received GP; cardiac function, histopathology, apoptosis, fibrosis/autophagy markers, and mitochondrial clearance were assessed. in vitro, Parkin-silenced hypoxic cardiomyocytes were used to evaluate GP's effects on viability, oxidative stress, mitochondrial function, autophagy proteins, and autophagosome formation. RESULTS: In vivo, GP improved cardiac function, reduced fibrosis/apoptosis, and suppressed fibrosis-related genes (Col1a1, Col3a1, Tgfb1, Mmp9). GP enhanced clearance of damaged mitochondria via autophagy, mitigating oxidative stress. in vitro, GP's protection against hypoxia required Parkin: it preserved mitochondrial homeostasis, inhibited ROS-mediated apoptosis, and reduced autophagosome accumulation. Mechanistically, GP attenuated excessive mitophagy by modulating Parkin, thereby maintaining mitochondrial quality and reducing oxidative injury. DISCUSSION: The mechanism by which GP regulates Parkin-dependent mitophagy identified in this study addresses the limitations of existing standard therapies that lack targeted regulation of mitochondrial quality. However, the upstream and downstream molecular regulatory mechanisms of the GP-Parkin pathway, as well as GP's long-term safety and pharmacokinetic interactions with standard drugs, remain to be further elucidated. Future studies may explore the synergistic efficacy and optimal dose ratio of GP combined with first-line drugs via in vitro liver microsome experiments and in vivo animal models, and conduct chronic toxicity studies to support its clinical translation. CONCLUSION: GP alleviates post-MI remodeling by suppressing Parkin-dependent hyperactivated mitophagy, reducing cardiomyocyte loss and fibrosis. Parkin is central to GP's therapeutic effects, highlighting its potential as a target for MI-related heart failure. This study elucidates GP's cardioprotective mechanism and proposes Parkin pathway modulation as a novel strategy to counteract pathological cardiac remodeling.