肝纤维化是肝病终末期前唯一可逆转的治疗时机。肝星状细胞在炎症刺激下转分化为肌成纤维细胞，导致细胞外基质（ECM）沉积是肝纤维化重要病理机制。本项目聚焦科学问题：溶血磷脂酰肌醇（LPI）/G蛋白偶联受体（GPR）55信号调控分子伴侣介导自噬（CMA）促进肝星状细胞转分化导致ECM沉积加剧肝纤维化的致病机制。预初实验发现肝纤维化患者外周血LPI表达显著升高；肝纤维化模型小鼠肝组织LPI及其受体GPR55表达上调；干预GPR55可抑制肝星状细胞转分化并缓解肝纤维化，且与肝星状细胞CMA有关。鉴此，本研究拟以肝脏磷脂代谢异常切入，解析LPI/GPR55活化规律；揭示LPI/GPR55信号通过抑制LAMP-2A转录和多聚体稳定性，抑制CMA靶向降解功能，促进肝星状细胞细胞骨架变化和转分化为肌成纤维细胞，导致ECM沉积加剧肝纤维化的致病作用和机制；探索干预LPI/GPR55为核心的肝纤维化防治新策略。

Liver fibrosis is the only definite reversible treatment opportunity before the end of liver disease. Hepatic stellate cells differentiate into myofibroblasts under the stimulation of inflammation, leading to extracellular matrix (ECM) deposition, which is an important pathological mechanism of liver fibrosis. The scientific issues, which this project focuses on, are that the role and regulatory mechanism of Lysophosphatidylinositol (LPI)/G protein coupled receptor (GPR) 55 signal regulating chaperone-mediated autophagy (CMA) of hepatic stellate cells, which leads to ECM deposition and promotes liver fibrosis. In the preliminary experiment, it was found that the expression of LPI in the peripheral blood of the patients with liver fibrosis was increased; the expression of LPI and its receptor GPR55 was up-regulated in liver tissue of liver fibrosis model mice. The intervention of GPR55 could inhibit the transdifferentiation of hepatic stellate cells and alleviate the liver fibrosis, which was related to the CMA of hepatic stellate cells. In light of this, LPI/GPR55 activation was analyzed from ligand source and receptor expression. The role of LPI/GPR55 in promoting ECM deposition leading to liver fibrosis was clarified. It was revealed that LPI/GPR55 signal can inhibit the targeted degradation of CMA, by inhibiting LAMP-2A transcription and polymer stability, promoting the transformation of hepatic stellate cells into myofibroblasts, which leads to ECM deposition. Solid evidence from this project will lay the foundation for a new strategy in the prevention and treatment of liver fibrosis.