Metformin attenuates myocardial ischemia/reperfusion-induced ferroptosis through the upregulation of Nur77-mediated IDH1.

Abstract

Current interventions for myocardial ischemia/reperfusion (I/R) injury focus on revascularization and the control of oxidative stress. Metformin can reduce I/R injury, with its protective effects extending beyond metabolic regulation. In this study, we investigated the cardioprotective mechanisms of metformin beyond AMPK activation, focusing on its effects on the Nur77-IDH1 axis. We employed myocardial I/R rat models and oxygen-glucose deprivation/reoxygenation in H9C2 cells, utilizing staining techniques, echocardiography, and molecular/cell-based assays. Metformin significantly mitigated myocardial I/R injury in rats, reducing PTGS2 expression, lowering iron content, decreased ROS accumulation, and increased mitochondrial function. Metformin also alleviated myocardial tissue damage and fibrosis and increased survival rates. In OGD/R-induced H9C2 cells, metformin suppressed ferroptosis, which could be reversed by Nur77 silencing. Metformin increased Nur77 and IDH1 expression by enhancing Nur77 translocation to the IDH1 promoter, inhibiting stress-related JNK/P38MAPK signaling. Catalytic site inhibitor IDH1 Inhibitor 5 (compound 2 AGI-5198) negated the protective effects of metformin. Collectively, these data reveal that metformin prevents myocardial I/R injury and ferroptosis through its effects on Nur77, IDH1 expression and inhibition of the JNK/P38 pathway. This highlights the novel therapeutic value of targeting ferroptosis with metformin to improve cardiac protection.