IRP2 m6A去甲基化修饰调节肝星状细胞铁死亡在肝纤维化中的作用和机制研究

铁死亡在抑制肝星状细胞（HSCs）活化减轻肝纤维化中有重要作用，但机制不明确。国内外研究和我们前期工作表明IRP2介导HSCs铁死亡。前期研究显示在肝纤维化小鼠肝脏组织和TGF-β活化的HSC-LX2细胞中，m6A修饰水平增加且FTO表达下降，而过表达FTO降低细胞活性和促进铁死亡；FTO表达与IRP2表达正相关且干扰METTL3降低IRP2 mRNA m6A修饰水平并上调IRP2；活化的HSC-LX2细胞中干扰YTHDF2抑制IRP2 mRNA降解。由此推测，FTO可能通过抑制m6A甲基化修饰介导的IRP2下调诱发HSC-LX2细胞中铁死亡信号，进而抑制细胞活化及肝纤维化。本项目拟通过建立肝纤维化小鼠和TGF-β或LPS活化的HSC-LX2细胞模型，从多层面研究FTO介导的IRP2 m6A去甲基化修饰调控HSCs铁死亡在肝纤维化中的作用和机制，旨在为肝纤维化防治提供新靶点。

Ferroptosis plays an important role in inhibiting the activation of hepatic stellate cells (HSCs) and alleviating liver fibrosis, but the mechanism is unclear. Recent studies and our previous studies indicate that IRP2 mediated the ferroptosis of HSCs. Our preliminary results indicated that in the liver tissues of liver fibrosis mice and TGF-β-activated HSC-LX2 cells, the modification level of m6A methylation was increased and FTO expression was decreased, while the overexpression of FTO decreased cell activity and promoted ferroptosis; the FTO expression was positively correlated with the IRP2 expression, and the interference with METTL3 decreased the modification level of IRP2 mRNA m6A methylation and increased the expression of IRP2. The interference with YTHDF2 in activated HSC-LX2 cells inhibited IRP2 mRNA degradation. Thus, we speculated that FTO might repress the activation of HSC-LX2 cells and the occurrence and development of liver fibrosis by inhibiting the down-regulation of IRP2 mediated by m6A methylation modification. In this study, the mouse model of liver fibrosis and TGF-β-activated or LPS-activated HSC-LX2 cell model will be established and are used to investigate the role and mechanism of IRP2 m6A demethylation mediated by FTO in regulating ferroptosis of HSCs in liver fibrosis, trying to provide the new targets for the prevention and treatment of liver fibrosis.