Muscone attenuates myocardial infarction by regulating ferroptosis of cardiomyocytes through Nrf2/system Xc-/GPX4 signaling pathway.

Acute myocardial infarction (MI) is among the diseases with the highest incidences and seriously threatens public health worldwide, with the present clinical treatment methods presenting considerable risks. Ferroptosis, characterized by iron dependence and intracellular oxidative accumulation, is a type of programmed cell death that has opened new avenues for treating MI. Muscone is one of the major active monomers of musk, which can improve ventricular remodeling after MI and myocardial ischemia-reperfusion injury. However, the ferroptosis mechanism underlying muscone-mediated MI treatment remains unelucidated. Therefore, this study aimed to investigate the mechanisms of action of muscone in MI management both in vivo and in vitro. Notably, muscone could attenuate MI injury, increase myocardial angiogenesis, and inhibit myocardial ferroptosis in the in vivo rat model. Furthermore, in vitro experiment results in rat cardiomyocytes H9c2 cells showed that muscone could inhibit hypoxia-induced cell damage, improve cell viability, and inhibit cell apoptosis and ferroptosis. Mechanistically, muscone-mediated ferroptosis inhibition was regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2)/System Xc-/glutathione peroxidase 4 (GPX4) signaling pathway to treat MI. Altogether, the results of this study show the therapeutic potential of muscone in MI treatment. These findings provide notable insights regarding the development of therapeutic approaches targeted at the Nrf2/System Xc- /GPX4 signaling pathway.