AUTHOR=Li Yilan , Yan Jingru , Zhao Qianqian , Zhang Yan , Zhang Yao TITLE=ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression JOURNAL=Frontiers in Pharmacology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.904314 DOI=10.3389/fphar.2022.904314 ISSN=1663-9812 ABSTRACT=

Sorafenib is the unique recommended molecular-targeted drug for advanced hepatocellular carcinoma, but its clinical use is limited due to cardiotoxicity. As sorafenib is an efficient ferroptosis inducer, the pathogenesis of this compound to ferroptosis-mediated cardiotoxicity is worth further study. Mice were administered 30 mg/kg sorafenib intraperitoneally for 2 weeks to induce cardiac dysfunction and Ferrostatin-1 (Fer-1) was used to reduce ferroptosis of mice with sorafenib-induced cardiotoxicity. Sorafenib reduced levels of anti-ferroptotic markers involving Slc7a11 and glutathione peroxidase 4 (GPX4), increased malonaldehyde malondialdehyde, apart from causing obvious mitochondria damage, which was alleviated by Fer-1. In vitro experiments showed that Fer-1 inhibited lipid peroxidation and injury of H9c2 cardiomyoblasts induced by sorafenib. Both in vitro and in vivo experiments confirmed that the expression of Slc7a11 was down regulated in sorafenib-induced cardiotoxicity, which can be partially prevented by treatment with Fer-1. Overexpression of Slc7a11 protected cells from ferroptosis, while knock-down of Slc7a11 made cardiomyoblasts sensitive to ferroptosis caused by sorafenib. Finally, by comparing data from the GEO database, we found that the expression of ATF3 was significantly increased in sorafenib treated human cardiomyocytes. In addition, we demonstrated that ATF3 suppressed Slc7a11 expression and promoted ferroptosis. Based on these findings, we concluded that ATF3/Slc7a11 mediated ferroptosis is one of the key mechanisms leading to sorafenib-induced cardiotoxicity. Targeting ferroptosis may be a novel therapeutic approach for preventing sorafenib-induced cardiotoxicity in the future.