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

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 expression and contribute to classical ferroptotic events. Consistently, phosphorylated STAT3 upregulation, ferritinophagy activation, and ferroptosis induction also occurred in HFD-fed mice and were responsible for HFD-induced cardiac injury. In addition, we found evidence that piperlongumine, a natural compound, effectively reduced phosphorylated STAT3 levels to protect cardiomyocytes from ferritinophagy-mediated ferrop...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Source Type: research