Tanshinone IIA Ameliorates Heart Failure by Inhibiting Ferroptosis via the Sirt1/p53/GPX4 Signaling Pathway.

Abstract

Heart failure (HF) is a high-mortality condition driven by cardiomyocyte death, and ferroptosis is a critical contributor to myocardial injury in this regard. Tanshinone IIA (Tan-IIA), a bioactive component from Salvia miltiorrhiza, has been shown to protect the heart, but its role in HF-related ferroptosis remains unclear. This study investigated whether Tan-IIA ameliorates HF by inhibiting ferroptosis and its underlying mechanism. We evaluated cardiac function, fibrosis, ferroptosis markers (such as ROS, Fe[Formula: see text], GSH, xCT, and GPX4), and Sirt1/p53 signaling using both a mouse model of HF induced by ligation of the left anterior descending (LAD) coronary artery and oxygen-glucose deprivation (OGD)-treated H9c2 cells. Direct binding of Tan-IIA to Sirt1 was verified by molecular docking, CETSA, and DARTS. Tan-IIA improved cardiac function, reduced fibrosis and inflammation, decreased ROS/Fe[Formula: see text], increased GSH, and upregulated xCT/GPX4 in vivo and in vitro. However, erastin reversed these effects. Tan-IIA upregulated Sirt1 and downregulated p53, while Sirt1 inhibition by EX527 abolished its cardioprotective and antiferroptotic actions. Tan-IIA ameliorates HF by inhibiting myocardial ferroptosis through the Sirt1/p53/GPX4 pathway thus in turn supports its potential clinical use in the treatment of HF.