Geniposide regulates mitochondrial dynamics and PINK1/Parkin-mediated mitophagy to mitigate myocardial ischemia–reperfusion injury in rats

Objective Myocardial ischemia-reperfusion injury (MIRI) significantly restricts the clinical efficacy of reperfusion therapy. Mitochondrial dysfunction represents the primary pathological mechanism underlying MIRI; however, pharmacological interventions targeting this pathway are limited. This study investigates whether Geniposide (GEN) mitigates MIRI by regulating mitochondrial dynamics and PINK1/Parkin-mediated mitophagy in rats. Methods A rat model of MIRI was established by 30 min of occlusion of the left anterior descending (LAD) coronary artery, followed by 6 h of reperfusion. GEN was administered intraperitoneally 2 h before model induction and again immediately upon reperfusion. After 6 h of reperfusion, cardioprotective efficacy of GEN was evaluated through assays, including echocardiography, 2,3,5-triphenyltetrazolium chloride (TTC) staining, enzyme-linked immunosorbent assay (ELISA), oxidative stress and myocardial injury marker quantification, mitochondrial function assessment, hematoxylin-eosin (HE) staining, transmission electron microscopy (TEM), immunofluorescence staining, and Western blot analysis. Results GEN treatment resulted in a significant reduction in infarct size compared to the I/R group (I/R+GEN: 29.22 ± 5.10% vs I/R: 38.48 ± 5.67%, P = 0.012). Cardiac function was preserved, as indicated by higher LVEF (I/R+GEN: 56.32 ± 5.88% vs I/R: 49.70 ± 3.74%, P = 0.029) and LVFS (I/R+GEN: 31.55 ± 3.46% vs I/R: 27.32 ± 2.19%, P = 0.027). Myocardial injury and oxidative stress were attenuated, demonstrated by reduced CK-MB, cTnI, LDH, MDA, and MPO levels, and increased SOD and GSH-Px (all P < 0.05). Mechanistically, GEN-treated hearts showed decreased Drp1 (P = 0.031) and increased MFN1 (P = 0.009), along with enhanced PINK1/Parkin-mediated mitophagy, as evidenced by an elevated LC3-II/I ratio (P < 0.001), decreased p62 (P = 0.002), and increased PINK1 and Parkin expression (both P < 0.01). Conclusions GEN is associated with reduced oxidative stress, altered mitochondrial dynamics, and increased markers of PINK1/Parkin-mediated mitophagy, which may contribute to its cardioprotective effects against MIRI.