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  • N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells.

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells.

Redox biology (2021-10-05)
Min Shen, Yujia Li, Yingqian Wang, Jiangjuan Shao, Feng Zhang, Guoping Yin, Anping Chen, Zili Zhang, Shizhong Zheng
ABSTRACT

Ferroptosis is a recently identified non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. However, the underlying exact mechanisms remain poorly understood. Here, we report that the total levels of N6-methyladenosine (m6A) modification are evidently increased upon exposure to ferroptosis-inducing compounds due to the upregulation of methylase METTL4 and the downregulation of demethylase FTO. Interestingly, RNA-seq shows that m6A modification appears to trigger autophagy activation by stabilizing BECN1 mRNA, which may be the potential mechanism for m6A modification-enhanced HSC ferroptosis. Importantly, YTHDF1 is identified as a key m6A reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent BECN1 plasmid-induced HSC ferroptosis. Noteworthy, YTHDF1 promotes BECN1 mRNA stability and autophagy activation via recognizing the m6A binding site within BECN1 coding regions. In mice, erastin treatment alleviates liver fibrosis by inducing HSC ferroptosis. HSC-specific inhibition of m6A modification could impair erastin-induced HSC ferroptosis in murine liver fibrosis. Moreover, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis and m6A modification in advanced fibrotic patients with hepatocellular carcinoma (HCC) receiving sorafenib monotherapy. Attractively, the m6A modification upregulation, autophagy activation, and ferroptosis induction occur in human HSCs. Overall, these findings reveal novel signaling pathways and molecular mechanisms of ferroptosis, and also identify m6A modification-dependent ferroptosis as a potential target for the treatment of liver fibrosis.

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