莪术醇调控CCF抗酒精性脂肪肝中肝细胞衰老的作用机制

酒精性脂肪肝（AFLD）目前国内外研究多聚焦于抑制肝细胞脂质堆积和细胞凋亡，忽略了肝细胞衰老及其相关机制在其中发挥的重要作用。我们前期工作初步表明，莪术醇（Curcumol）可有效抑制酒精诱导的肝细胞衰老及胞质染色质碎片（CCF）的形成。本项目创新性的提出Curcumol可能通过调控CCF的形成抑制肝细胞衰老进而具有抗AFLD的作用。为此，本研究拟利用酒精建立体内外AFLD模型，首先明确Curcumol调控衰老相关分泌表型（SASP）细胞因子分泌与肝细胞衰老相关；然后利用质粒转染、基因沉默等技术研究Curcumol通过CCF-cGAS-STING调控SASP细胞因子分泌继而抑制肝细胞衰老的分子机制，并明确CCF的形成是否依赖于LC3-lamin B1相互作用。以此从新的视角阐明Curcumol具有抗AFLD的作用及分子机制，预期研究成果有望为Curcumol防治AFLD提供新策略和新靶点。

The current researches of alcoholic fatty liver disease (AFLD) are mainly focus on inhibition of lipid accumulation and induction of hepatocyte apoptosis. Senescence of hepatocyte and the related molecular mechanisms are rarely investigated. Our previous studies showed that curcumol could potently suppress alcohol-induced hepatocyte senescence and the formation of cytoplasmic chromatin fragments (CCF). We herein creationally put forward that curcumol has effects on AFLD associated with inhibition of cellular senescence by regulating the formation of CCF. To test these hypotheses, we first use the in vivo and in vitro AFLD model to investigate the correlation between the regulation of senescence associated secretory phenotype (SASP) cytokine secretion and senescence of hepatocyte under curcumol treatment. Then we use the plasmid transfection and gene silencing technologies to further study the molecular mechanism of repression of hepatocyte senescence by which curcumol regulates SASP cytokine secretion through CCF-cGAS-STING. Finally, Based on the establishment of the critical role of CCF-cGAS-STING in curcumol intervention of senescence of hepatocyte, we attempt to elucidate whether this effect is associated with LC3-lamin B1 interaction. Through these studies, we can interpret the actions of curcumol on hepatocyte senescence and elucidate the underlying molecular mechanisms. These studies provide basis for developing curcumol as promising anti-AFLD agent for clinical application.