线粒体来源的DAMPs激活肝星状细胞自噬参与肝纤维化的分子机制研究

我们前期研究首次证明受损肝细胞线粒体来源的损伤相关分子模式（mito-DAMPs）通过直接激活肝星状细胞（HSCs）促进肝纤维化发生，但分子机制不清。基于细胞自噬参与HSCs激活而促进肝纤维化，我们进一步应用细胞实验证实mito-DAMPs促进HSCs自噬且下调糖原合成酶激酶3β（GSK3β）活性，上调GSK3β活性可下调HSCs自噬。因此提出研究假说：mito-DAMPs通过GSK3β分子激活HSCs自噬促进肝纤维化。为验证推测：①在细胞水平，探讨mito-DAMPs对HSCs自噬的调控；②在细胞水平，探讨mito-DAMPs是否介导GSK3β激活HSCs自噬；③应用动物模型，探讨GSK3β介导自噬在mito-DAMPs促进肝纤维化中的作用；④收集临床病例，验证mito-DAMPs与肝纤维化程度相关性。本研究有望阐明mito-DAMPs参与肝纤维化发生的分子机制，为其诊治提供新线索。

We previously discovered that hepatocyte mitochondrial-derived damage-related molecular patterns (mito-DAMPs) promote liver fibrosis by directly activating hepatic stellate cells (HSCs), but the molecular mechanism is unclear. Previous studies have shown that autophagy participates in the activation of hepatic stellate cells (HSCs) to promote liver fibrosis. We further applied cell experiments to confirm that mito-DAMPs promote HSCs autophagy and down-regulate glycogen synthase kinase 3β (GSK3β) activity, and up-regulating GSK3β activity can down-regulate HSCs autophagy. Therefore, we propose the hypothesis that mito-DAMPs activate HSCs autophagy through GSK3β to promote liver fibrosis.. To verify the speculation, we prepare to explore the regulation of mito-DAMPs on HSCs autophagy at the cellular level firstly. Secondly, we aim to explore whether mito-DAMPs mediate GSK3β to activate HSCs autophagy at the cellular level. Then, we will use animal models to explore the role of mito-DAMPs regulating HSCs autophagy in the process of liver fibrosis. Finally, samples of clinical cases of liver fibrosis will be collected to verify the corresponding relationship between mito-DAMPs and liver fibrosis. This study is expected to clarify the molecular mechanism of mito-DAMPs involved in the occurrence of liver fibrosis, and provide new clues for the diagnosis and treatment of liver fibrosis.