Nrf2/GPX4-Dependent Ferroptosis Inhibition: The Central Mechanism Underpinning Germacrone-Induced Cardioprotection in...

Myocardial infarction (MI) involves a pathological process in which its association with ferroptosis is notably pronounced, and targeted regulation of ferroptosis presents a promising approach for treating MI. This work delineates the molecular basis by which the natural sesquiterpene germacrone protects against cardiomyocyte ferroptosis following isoproterenol (ISO)-induced MI. We established a murine model of ISO-induced MI, paired with an injured H9c2 cardiomyocyte model in vitro. Mice in the experimental group received daily oral germacrone (25, 50, and 100 mg/kg) for 7 consecutive days. We profiled myocardial injury markers and key nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) axis proteins. The mechanism of action was confirmed by utilizing ML385, the Nrf2-specific inhibitor. Germacrone significantly reduced ISO-induced myocardial injury in mice, improving cardiac function and decreasing myocardial histopathological damage. Germacrone universally attenuated the elevation of myocardial injury and inflammatory markers in all experimental models. It also decreased the apoptosis rate of H9c2 cells. Germacrone inhibited myocardial ferroptosis and upregulated the abundance of pivotal regulatory proteins, including Nrf2, GPX4, and heme oxygenase-1 (HO-1), along with solute carrier family 7 member 11 (SLC7A11). ML385, an Nrf2 antagonist, can block germacrone's protective effect against ISO-induced myocardial ferroptosis and reverse its upregulation of these pathway proteins. These findings provide a new potential target and experimental foundation for MI treatment.