双氢青蒿素通过核受体Rev-Erbα调控肝星状细胞脂噬与铁死亡的抗肝纤维化机制研究

肝星状细胞（HSC）活化是肝纤维化的核心环节，其细胞自噬和铁死亡在肝病中起重要作用，是目前国内外研究热点。但胞内脂滴改变的前因后果尚不清楚。我们前期发现调控生物节律的核受体Rev-Erbα与HSC脂滴基因、自噬基因的表达呈节律相关性，Rev-Erbα激动剂可恢复HSC脂滴、阻断自噬并抑制HSC活化；还发现双氢青蒿素（DHA）可激动Rev-Erbα并诱导HSC铁死亡。但有关DHA可能通过Rev-Erbα调控HSC脂噬与铁死亡改善肝纤维化病变目前未见报道。本项目拟以转基因动物的体内外模型及多学科技术，明确HSC脂滴变化与肝纤维化相关，解析脂滴中甘油三酯自噬的作用；阐明Rev-Erbα对HSC脂噬及铁死亡的节律性调控机制及因果关系；最后明确DHA通过Rev-Erbα发挥抗肝纤维化作用。本项目将明确Rev-Erbα的靶标作用并拓展DHA在肝病领域的应用，为通过调控生物节律干预肝纤维化提供明确依据。

Hepatic stellate cell (HSC) activation is the central event in the pathogenesis of liver fibrosis. HSC autophagy and ferroptosis play important roles in liver diseases, which is a hot research area. However, little is known about the reasons and consequences of alterations in the intracellular lipid droplets of HSCs. We previously discovered that the nuclear receptor Rev-Erbα, a well-established circadian rhythm molecule, had closely related rhythmic expression with the lipid droplet genes and autophagy genes in HSCs. Rev-Erbα agonist could restore lipid droplets and block autophagy in HSCs, leading to inhibition of HSC activation. In addition, we found that the clinical drug dihydroartemisinin (DHA) could activate Rev-Erbα and induce ferroptosis in HSCs. Currently, there are no literature reports about DHA regulation of HSC lipophagy and ferroptosis for mitigating liver fibrotic injury. The present project will use transgenic animals with liver fibrosis induced by distinct mechanisms, a variety of in vivo and in vivo model systems, and multidisciplinary approaches to determine the relevance of HSC lipid droplet alteration to liver fibrogenesis, analyze the role of autophagy of lipid droplet triglyceride in the pathogenesis of disease, elucidate the mechanisms underlying Rev-Erbα regulation of HSC lipophagy and ferroptosis as well as the causal relationship, and finally validate the antifibrotic effects of DHA through Rev-Erbα. This project will establish the target role of Rev-Erbα and extent the potential application of DHA in the field of chronic liver diseases, and more importantly provide clear evidence for intervention of liver fibrosis through modulating circadian rhythm.