Abstract：
Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.
摘要：
肝纤维化影响全球约8亿患者，每年有超过200万人死亡。然而，没有批准的药物用于治疗肝纤维化。在这项研究中,我们研究了银杏素对肝纤维化的影响及其潜在机制。在硫代乙酰胺或胆管结扎诱导的小鼠模型中评估银杏素对肝纤维化的影响。对人LX-2细胞和原代小鼠肝星状细胞（HSC）进行实验，以探讨其潜在的机制，这也在小鼠模型中得到了验证。在硫代乙酰胺（TAA）和胆管结扎（BDL）诱导的纤维化模型中，银杏素显着降低了肝胞外基质沉积和HSC活化。在抑制肝脏炎症和改善肝功能方面也存在有益作用。体外实验表明，银杏素能明显抑制HSC的活力，并剂量依赖性地诱导HSC凋亡。机制研究表明，银杏素的抗纤维化作用取决于STAT1的激活，因为STAT1沉默后在体外和氟达拉滨抑制STAT1激活后在体内消失。此外，我们观察到HSC和肝细胞之间有意义的交叉对话，其中IL-6由银杏素诱导的凋亡HSC释放，通过激活STAT3信号增强肝细胞增殖。银杏素通过STAT1激活诱导HSC凋亡而表现出抗纤维化作用，并通过IL-6/STAT3途径增强HSC凋亡继发的肝细胞增殖。
