Pterostilbene Attenuates Heart Failure by Inhibiting Myocardial Ferroptosis Through SIRT1/GSK-3β/GPX4 Signaling Pathway

Sustained myocardial injury due to hypertension and diabetes mellitus leads to production of endogenous reactive oxygen species (ROS) and insufficient myocardial antioxidant capacity, increasing the risk of cardiomyocyte ferroptosis. Ferroptosis is a nonapoptotic form of cell death driven by unrestricted lipid peroxidation. Dysfunction of the glutathione peroxidase 4 (GPX4) antioxidant system also plays an important role in ferroptosis. Cardiomyocyte ferroptosis ultimately leads to myocardial deterioration, such as inflammation, fibrosis, and cardiac remodeling, resulting in structural and functional changes. Pterostilbene (PTS), a demethylated derivative of resveratrol, exhibits strong anti-inflammatory and antioxidative activities. In this study, we used experiments to explore ferroptosis induced by angiotensin II (Ang II) of primary cardiac myocytes (CMs) and experiments to prepare a transverse aortic constriction (TAC)-induced cardiac dysfunction mouse model. PTS can significantly ameliorate Ang II-induced cardiomyocyte ferroptosis and reduce cardiac remodeling, while improving cardiac function in mice after TAC . Further mechanistic investigations revealed that PTS exerts its protective effect through the SIRT1/GSK-3β/GPX4 pathway. After siRNA-mediated knockdown of SIRT1 or GPX4 in CMs, the protective effects of PTS on cardiomyocytes were abolished. This study provides important theoretical support for the potential of PTS to attenuate pathological cardiac remodeling and heart failure and provides a preliminary exploration of the molecular pathways involved in its protective mechanism.