Puerarin reduces susceptibility to ventricular arrhythmias and inhibits ferroptosis via Sirt1/Nrf2 signaling in high-fat-diet rats.

Obesity is a significant risk factor for cardiac arrhythmias, and the ferroptosis is closely related to cardiac arrhythmias. This study aimed to investigate whether puerarin (Pue), a natural isoflavone, could reduce the susceptibility to ventricular arrhythmias (VAs) associated with obesity and inhibit ferroptosis, with a particular focus on the Sirt1/Nrf2 signaling pathway. Male rats were randomly divided into three groups: normal chow diet (NC), high-fat diet (HFD), and HFD with Pue treatment (100mg/kg, HFD + Pue). After 16 weeks, electrophysiological, structural, and molecular analysis were performed. Compared to the NC group, HFD rats exhibited prolonged QT interval and Tpeak-Tend interval, amplified transmural dispersion of ventricular repolarization, and increased susceptibility to VAs. Pue treatment significantly ameliorated these electrophysiological abnormalities and reduced VAs susceptibility. HFD rats showed cardiac hypertrophy, fibrosis, and inflammation, which were alleviated by Pue application. Cardiac lipid peroxidation, iron deposition, mitochondrial abnormality, and ferroptosis marker induction were observed in HFD rats. Further, treatment with Pue improved these alterations. Additionally, molecular docking analysis confirmed the interaction of Pue with Sirt1 and Nrf2. Furthermore, Pue treatment upregulated Sirt1 and Nrf2 expression in HFD rats, thereby reducing reactive oxygen species (ROS) generation and ferroptosis. Moreover, Pue protected cardiomyocytes against palmitic acid (PA)-induced injury by inhibiting ferroptosis via the Sirt1/Nrf2 pathway in H9c2 cells. Overall, our study shows for the first time that Pue reduces susceptibility to VAs and inhibits ferroptosis in HFD rats by modulating the Sirt1/Nrf2 signaling pathway, offering a potential therapeutic strategy for obesity-related cardiac arrhythmias.