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

Area of Science:

• Cardiovascular Biology
• Cell Death Mechanisms
• Pharmacology

Background:

• Heart failure (HF) is a major cause of mortality linked to cardiomyocyte death.
• Ferroptosis, a specific form of regulated cell death, significantly contributes to myocardial injury in HF.
• Tanshinone IIA (Tan-IIA), derived from Salvia miltiorrhiza, shows cardioprotective effects, but its role in HF-related ferroptosis is not well understood.

Purpose of the Study:

• To investigate whether Tan-IIA ameliorates heart failure by inhibiting ferroptosis.
• To elucidate the underlying molecular mechanisms of Tan-IIA's action in HF and ferroptosis.

Main Methods:

• Utilized a mouse model of HF induced by LAD ligation and oxygen-glucose deprivation (OGD) in H9c2 cells.
• Assessed cardiac function, fibrosis, ferroptosis markers (ROS, Fe, GSH, xCT, GPX4), and Sirt1/p53 signaling.
• Employed molecular docking, CETSA, and DARTS to confirm direct binding of Tan-IIA to Sirt1.

Main Results:

• Tan-IIA improved cardiac function, reduced fibrosis and inflammation in HF models.
• Tan-IIA decreased reactive oxygen species (ROS) and iron levels while increasing glutathione (GSH) and upregulating xCT and GPX4, key ferroptosis regulators.
• Tan-IIA upregulated Sirt1 and downregulated p53; Sirt1 inhibition abolished its protective effects, while erastin reversed its benefits.

Conclusions:

• Tan-IIA ameliorates heart failure by inhibiting myocardial ferroptosis.
• The cardioprotective and anti-ferroptotic effects of Tan-IIA are mediated through the Sirt1/p53/GPX4 signaling pathway.
• Tan-IIA demonstrates potential for clinical application in treating heart failure.