STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice

作者：Mengying Zhu, Lulu Peng, Shengqi Huo, Dewei Peng, Junyi Gou, Wei Shi, Jingwen Tao, Tao Jiang, Yue Jiang, Qian Wang, Bingyu Huang, Lintong Men, Sheng Li, Jiagao Lv, Li Lin · 发表于：Free Radical Biology and Medicine · 年份：2023 · DOI：10.1016/j.freeradbiomed.2023.03.003 · 被引用次数：132 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、RNA modifications and cancer

High-fat diet (HFD) intake provokes obesity and cardiac anomalies. Recent studies have found that ferroptosis plays a role in HFD-induced cardiac injury, but the underlying mechanism is largely unclear. Ferritinophagy is an important part of ferroptosis that is regulated by nuclear receptor coactivator 4 (NCOA4). However, the relationship between ferritinophagy and HFD-induced cardiac damage has not been explored. In this study, we found that oleic acid/palmitic acid (OA/PA) increased the level of ferroptotic events including iron and ROS accumulation, upregulation of PTGS2 mRNA and protein levels, reduced SOD and GSH levels, and significant mitochondrial damage in H9C2 cells, which could be reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Intriguingly, we found that the autophagy inhibitor 3-methyladenine mitigated OA/PA-induced ferritin downregulation, iron overload and ferroptosis. OA/PA increased the protein level of NCOA4. Knockdown of NCOA4 by SiRNA partly reversed the reduction in ferritin, mitigated iron overload and lipid peroxidation, and subsequently alleviated OA/PA-induced cell death, indicating that NCOA4-mediated ferritinophagy was required for OA/PA-induced ferroptosis. Furthermore, we demonstrated that NCOA4 was regulated by IL-6/STAT3 signaling. Inhibition or knockdown of STAT3 effectively reduced NCOA4 levels to protect H9C2 cells from ferritinophagy-mediated ferroptosis, whereas STAT3 overexpression by plasmid appeared to increase NCOA4 express...