Cell Signal. 2026 Aug 8:112802. doi: 10.1016/j.cellsig.2026.112802. Online ahead of print.
ABSTRACT
Diabetic cardiovascular disease remains the leading cause of mortality in patients with diabetes, underscoring the urgent need for effective therapeutic strategies to improve clinical outcomes and prevent major adverse cardiovascular events in this high-risk population. Metformin, a widely prescribed antihyperglycemic agent, not only lowers blood glucose levels but also modulates multiple intracellular signaling pathways, thereby exerting pleiotropic effects. The present study aimed to evaluate the cardioprotective effects of metformin and elucidate its underlying molecular mechanisms in myocardial ischemia-reperfusion injury. Accordingly, we established in vivo diabetic models and in vitro hyperglycemic conditions to assess the effects of metformin on myocardial tissue in diabetes. The results demonstrated that metformin treatment significantly ameliorated cardiac dysfunction and attenuated myocardial morphological abnormalities in diabetic rats subjected to ischemia-reperfusion, and concurrently improved cardiomyocyte viability under hyperglycemic conditions. Moreover, metformin enhanced autophagy, promoted mitophagic activity, and restored mitochondrial homeostasis-effects that were further validated using compound C in cultured cardiomyocytes under hyperglycemic conditions. Collectively, these findings indicate that metformin confers cardioprotection against myocardial ischemia-reperfusion injury (MIRI) through activation of AMP-activated protein kinase (AMPK) and its downstream signaling cascades, thereby regulating mitophagic processes.
PMID:42570748 | DOI:10.1016/j.cellsig.2026.112802