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

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

  • Free Radic Biol Med. 2023 Mar 18;S0891-5849(23)00102-8. doi: 10.1016/j.freeradbiomed.2023.03.003.
Mengying Zhu 1 Lulu Peng 1 Shengqi Huo 1 Dewei Peng 1 Junyi Gou 1 Wei Shi 1 Jingwen Tao 1 Tao Jiang 2 Yue Jiang 1 Qian Wang 1 Bingyu Huang 1 Lintong Men 1 Sheng Li 1 Jiagao Lv 1 Li Lin 3
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Division of Geriatrics, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: linlee271227@163.com.
Abstract

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.

Keywords

Ferritinophagy; Ferroptosis; HFD-Induced cardiac injury; Obesity; Reactive oxygen species (ROS); STAT3.

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