Ginsenoside C3 alleviates myocardial ischemia/reperfusion injury by inhibiting TRPM7 and activating the Nrf2-Keap1-HO-1 signaling pathway

Abstract Aims: Ginsenosides are major bioactive components of ginseng and have been demonstrated to provide protective activity against injury triggered by myocardial ischemia/reperfusion (MIRI). Drawing on the structural attributes of naturally occurring ginsenosides, we synthesized a novel ginsenoside derivative, Compound 3 (C3). This investigation aimed to evaluate the protective effects of C3 against MIRI and to clarify the molecular mechanism underlying its action. Materials and methods: In vivo and ex vivo rat MIRI models were established. Both models were subjected to 30 min ischemia followed by reperfusion. Cardiac functional indices, including LVDP, LVEDP, and ±dp/dtmax, were recorded to evaluate cardiac function. Myocardial infarct size, LDH activity, MDA levels, and SOD activity was measured to assess myocardial damage and oxidative stress. HE staining enabled observation of myocardialmorphological changes. Cardiomyocyte apoptosis was detected via TUNEL assay. Finally, Western blot quantified protein expression of TRPM7, Bax, Bcl-2, Cleaved-Caspase3, Keap1, Nrf2, HO-1. Results: In MIRI models, C3 treatment significantly restored impaired cardiac function, reduced histopathological injury, and suppressed oxidative stress. C3 markedly inhibited TRPM7 expression, promoted activation of the Nrf2-Keap1-HO-1 antioxidant pathway, and lessened apoptosis in cardiomyocytes. The TRPM7 inhibitor NS8593 recapitulated the cardioprotective effects of C3, whereas the TRPM7 agonist MIB abrogated C3-mediated protection. Significance: This study demonstrates that the novel ginsenoside derivative C3 alleviates MIRI via attenuation of oxidative stress and decreased cardiomyocyte apoptosis. Mechanistically, C3 inhibits TRPM7, which in turn promotes activation of the downstream Nrf2–Keap1–HO-1 cascade. These findings offer preclinical evidence that C3 represents a promising agent for MIRI therapy.