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

Mar 20, 2023Free radical biology & medicine

STAT3 signaling may increase heart damage by boosting cell iron breakdown and iron-related cell death in mice on a high-fat diet

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Abstract

High-fat diet intake is associated with increased ferroptosis in cardiac cells due to the activation of specific cellular processes.

Oleic acid/palmitic acid exposure led to elevated levels of iron and reactive oxygen species (ROS), upregulation of PTGS2, and mitochondrial damage in heart cells.
Inhibition of ferroptosis using ferrostatin-1 reversed the observed cellular damage caused by oleic acid/palmitic acid.
Nuclear receptor coactivator 4 (NCOA4) was found to play a role in reducing ferritin levels and promoting ferroptosis in heart cells exposed to oleic acid/palmitic acid.
IL-6/STAT3 signaling was identified as a regulator of NCOA4, where inhibition or knockdown of STAT3 decreased NCOA4 levels and offered protection against ferroptosis.
Piperlongumine reduced phosphorylated STAT3 levels and provided protection to heart cells from ferroptosis in both laboratory and animal models.

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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 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 ferroptosis both in vitro and in vivo. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis was one of the critical mechanisms contributing to HFD-induced cardiac injury. The STAT3/NCOA4/FTH1 axis might be a novel therapeutic target for the treatment of HFD-induced cardiac injury.

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

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