Matrine induces cardiotoxicity by promoting ferroptosis through the Nrf2 antioxidant system in H9c2 cells

Matrine (MT) has shown promising efficacy in various cancers and chronic hepatitis; however, its clinical application is limited because of its side effects. Our previous studies have indicated that MT can induce severe hepatotoxicity and nephrotoxicity. The current study aimed to investigate its cardiotoxicity and potential underlying mechanisms in H9c2 cells. Our results showed that MT induced H9c2 cell death and disrupted the cellular membrane integrity. Moreover, MT decreased glutathione (GSH) and cysteine (Cys) levels, and increased Fe2+, lipid peroxidation, reactive oxygen species (ROS), and MDA levels, ultimately leading to ferroptosis. Interestingly, these phenomena were alleviated by the ferroptosis inhibitor Fer-1, whereas MT-induced ferroptosis was exacerbated by the ferroptosis agonist RSL3. In addition, MT significantly reduced FTH, Nrf2, xCT, GPX4, and FSP1 protein levels and inhibited the transcriptional activity of Nrf2 while increasing TFR1 protein levels. Supplementation with Nrf2 agonist (Dimethyl fumarate, DMF) or selenium (Sodium selenite, SS) and CoQ10 alleviated MT-induced cytotoxic effects in H9c2 cells. These results suggest that ferroptosis, which is mediated by an imbalance in the Nrf2 antioxidant system, is involved in MT-induced cardiac toxicity. [Display omitted] •Matrine (MT) has potential cardiotoxicity.•The cardiotoxic effects of MT involve disruption of redox homeostasis.•The cardiotoxicity of MT involves Nrf2 antioxidant system-mediated ferroptosis.•Nrf2 may be a protective target for the treatment of MT-induced cardiotoxicity.