Zian Wang, Xuan Liu, Yunjie Wu, Guangjian Chen, J. Wang, Yuewen Qi, Roger Wu, Jiancheng Wang, Qinghai Meng, Li Yu
Heart failure (HF) remains a prevalent complication following myocardial infarction (MI), characterized by mitochondrial dysfunction and cardiomyocyte ferroptosis, which jointly contribute to myocardial remodeling and impaired cardiac function. The present study aims to evaluate the cardioprotective efficacy and underlying mechanisms of trimetazidine (TMZ), a clinically established anti-anginal agent, in alleviating post-MI HF regulation of mitochondrial quality control and ferroptosis inhibition. Utilizing an in vivo mouse model established by left coronary artery ligation, TMZ administration significantly improved cardiac function, delayed ventricular remodeling, and reduced myocardial infarct size. Concurrently, TMZ treatment significantly reduced myocardial oxidative stress, evidenced by elevated antioxidant enzyme levels (GSH and SOD), decreased malondialdehyde (MDA), and lower intracellular Fe 2+ accumulation, along with upregulation of key anti-ferroptotic markers GPX4 and SLC7A11. Complementary in vitro experiments on oxygen-glucose deprivation (OGD)-injured HL-1 cardiomyocytes confirmed that TMZ preserved cellular viability in a dose-dependent manner by inhibiting ferroptosis. Furthermore, TMZ effectively restored mitochondrial membrane potential, improved mitochondrial morphology, promoted mitophagy by increasing PINK1/Parkin pathway activation, and corrected mitochondrial dynamics through upregulation of MFN1 and downregulation of DRP1. Notably, when the mitophagy inhibitor Mdivi-1 or PINK1 siRNA was used, the protective effect of TMZ was reversed by inhibition of mitophagy. This suggests that mitophagy activated through PINK1/Parkin signaling is essential for TMZ-mediated myocardial protection and ferroptosis suppression. Molecular docking further validated TMZ's potential direct interaction with PINK1. In conclusion, these findings demonstrate that TMZ ameliorates post-MI heart failure by orchestrating mitochondrial quality control through promotion of mitophagy and suppression of GPX4-dependent ferroptosis, offering novel mechanistic insight into its therapeutic potential in the management of ischemic heart disease.