Celastrol confers ferroptosis resistance via AKT/GSK3β signaling in high-fat diet-induced cardiac injury.

Obesity-induced cardiac dysfunction is a severe global disease associated with high dietary fat intake, and its pathogenesis includes inflammation, oxidative stress, and ferroptosis. Celastrol (Cel) is a bioactive compound isolated from the herb Tripterygium wilfordii , which has a protective influence on cardiovascular diseases. In this study, the role of Cel in obesity-induced ferroptosis and cardiac injury was investigated. We found that Cel alleviated ferroptosis induced by Palmitic acid (PA), exhibiting a decrease in the LDH, CK-MB, Ptgs2, and Lipid Peroxidation levels. After cardiomyocytes were treated with additional LY294002 and LiCl, Cel exerted its protective effect through increased AKT/GSK3β phosphorylation and decreased level of lipid peroxidation and Mitochondrial ROS. The systolic left ventricle (LV) dysfunction of obese mice was alleviated via ferroptosis inhibition by elevated p-GSK3β and decreased Mitochondrial ROS under Cel treatment. Moreover, mitochondrial anomalies included swelling and distortion in the myocardium which was relieved with Cel. In conclusion, our results demonstrate that ferroptosis resistance with Cel under HFD conditions targets AKT/GSK3β signaling, which provides novel therapeutic strategies in obesity-induced cardiac injury. [Display omitted] • Celastrol suppresses PA-induced ferroptosis in cardiomyocytes. • Celastrol resists PA-induced cardiotoxicity by targeting AKT/GSK3β signaling. • Celastrol upregulates GSK3β phosphorylation and NRF2 expression in HFD mice. [ABSTRACT FROM AUTHOR]