MAFG调控肝星状细胞铁死亡在肝纤维化中的作用及其机理研究

肝纤维化临床发病率高且发病机制尚不明确。肝星状细胞的活化增殖是肝纤维化的中心环节，但由于肝星状细胞激活受多种因素影响，抑制肝星状细胞激活在肝纤维化进程中疗效有限，因此探究活化状态肝星状细胞死亡的调控机制对于肝纤维化的治疗具有重要意义。本课题组前期研究发现MAFG在肝纤维化的临床标本中表达增高，且MAFG影响驱动铁死亡的重要因子GSH的水平。以此为基础，本项目将系统性研究MAFG的临床意义；阐明MAFG在肝纤维化发生发展和铁死亡中的作用，明确MAFG上游调控分子miR-29通过靶向抑制MAFG调控肝星状细胞铁死亡的分子机制；进一步研究在肝星状细胞中MAFG为SAMe和UDCA的作用靶点，并通过SAMe联合UDCA更大程度地促进肝星状细胞的铁死亡和抑制活化状态肝星状细胞的增殖，最终达到抗肝纤维化的重要作用，为临床肝纤维化的治疗提供新的思路。

Liver fibrosis has high clinical incidence and unclear pathogenesis. The activation and proliferation of hepatic stellate cell plays a central role in the pathological process of liver fibrosis. Since hepatic stellate cell activation is affected by many factors and the inhibition of hepatic stellate cell activation has limited efficacy, investigating the mechanism of regulating HSC death is of great significance for the treatment of liver fibrosis. Research team previous study found the expression of MAFG is increased in clinical specimens of liver fibrosis and MAFG affects the level of GSH that is an important factor driving ferroptosis. Based on these results and studies, our project will systematically study the clinical significance of MAFG; illustrate the role of MAFG in the development of liver fibrosis and ferroptosis; clarify the molecular mechanism of MAFG, targeted by upstream regulator miR-29, regulating the ferroptosis of hepatic stellate cell; to further study that MAFG is the drug target of SAMe and UDCA in hepatic stellate cells; comfirm that the combination of SAMe and UDCA promote the ferroptosis of hepatic stellate cells and inhibit the proliferation of activated hepatic stellate cells to greater extent, which will finally reverse fibrosis. Our project will provide new ideas for the treatment of liver fibrosis.