Ferroptosis mediated by the interaction between Mfn2 and IREα promotes arsenic-induced nonalcoholic steatohepatitis

• Published in: Environmental research 2020-09, Vol.188, p.109824, Article 109824
• Main Authors: Wei, Sen, Qiu, Tianming, Wang, Ningning, Yao, Xiaofeng, Jiang, Liping, Jia, Xue, Tao, Ye, Zhang, Jingyuan, Zhu, Yuhan, Yang, Guang, Liu, Xiaofang, Liu, Shuang, Sun, Xiance
• Format: Article
• Language: English
• Subjects: ACSL4; Animals; Arsenic; Arsenic - toxicity; Coenzyme A Ligases; Endoribonucleases - drug effects; Endoribonucleases - physiology; Ferroptosis; GTP Phosphohydrolases - drug effects; GTP Phosphohydrolases - physiology; Mitochondrial Proteins - drug effects; Mitochondrial Proteins - physiology; Multienzyme Complexes - drug effects; Multienzyme Complexes - physiology; NASH; Non-alcoholic Fatty Liver Disease - chemically induced; Protein Serine-Threonine Kinases - drug effects; Protein Serine-Threonine Kinases - physiology; Rats
• ISSN: 0013-9351; 1096-0953
• DOI: 10.1016/j.envres.2020.109824

Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro, we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH. •Ferroptosis is involved in NaAsO2-induced nonalcoholic steatohepatitis.•NaAsO2-induced ferroptotic cell death depends on the interaction of Mfn2 and IRE1α.•The ACSL4 plays a leading role in the progression of ferroptosis induced by NaAsO2 via manipulating 5-HETE content.