Trimetazidine alleviates heart failure after myocardial infarction by promoting PINK1/parkin-mediated mitophagy and suppressing GPX4-dependent ferroptosis

Nov 15, 2025European journal of pharmacology

Trimetazidine helps heart failure after heart attack by boosting damaged mitochondria removal and reducing cell death caused by iron

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Abstract

Trimetazidine (TMZ) administration significantly improved cardiac function and reduced myocardial infarct size in a mouse model of post-myocardial infarction heart failure.

TMZ treatment delayed ventricular remodeling and reduced myocardial oxidative stress, indicated by increased antioxidant enzyme levels and decreased malondialdehyde.
The administration of TMZ led to lower intracellular iron accumulation and upregulation of anti-ferroptotic markers GPX4 and SLC7A11.
In vitro studies showed that TMZ preserved cellular viability in cardiomyocytes injured by oxygen-glucose deprivation in a dose-dependent manner by inhibiting ferroptosis.
TMZ restored mitochondrial membrane potential and improved mitochondrial morphology, promoting mitophagy through activation of the PINK1/Parkin pathway.
Inhibition of mitophagy using Mdivi-1 or PINK1 siRNA reversed the protective effects of TMZ, suggesting that mitophagy is crucial for its cardioprotective action.

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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 Feaccumulation, 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. 2+

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Trimetazidine alleviates heart failure after myocardial infarction by promoting PINK1/parkin-mediated mitophagy and suppressing GPX4-dependent ferroptosis

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