Liver fibrosis is characterized by formation of scar tissue in the liver. The role of STAT3 signaling has been implicated on activating hepatic stellate cells (HSC) to myofibroblast-like cells in liver fibrosis. Major factors that activate STAT3 signaling are TGF-β1 and IL-6, which are upregulated in the liver in patients afflicted with liver fibrosis. Recent reports indicate that not only IL-6, but also the non-canonical signaling pathway of TGF-β1 is associated with STAT3 signaling. In this study, we demonstrate a new function of the STAT3 inhibitor, STX-0119, in liver fibrosis. STX-0119 is an inhibitor of STAT3 dimerization, which is required for nuclear localization of STAT3. We first investigated the anti-fibrotic effect of STX-0119 in in vitro experiments. Exposure to STX-0119 inhibited the nuclear localization of STAT3 in HSCs, resulting in decreased expression of its target genes, such as col1a1 and αSMA. In addition, STX-0119 also inhibited the TGF-β1/IL-6-induced activation of HSCs. Next, we examined the in vivo effect of STX-0119 in the liver fibrosis mouse model using thioacetamide (TAA) and carbon tetrachloride (CCl4). STX-0119 attenuated the TAA-induced liver fibrosis by inhibiting activation of HSCs to myofibroblast-like cells. Consistent with the in vivo results using TAA-induced liver fibrosis model, treatment of STX-0119 similarly attenuated CCl4-induced liver fibrosis. In conclusion, we believe that STX-0119 inhibits the development of liver fibrosis by blocking the activation of hepatic stellate cells. These results indicate that STX-0119 is a potential new therapeutic strategy to prevent disease progression to cirrhosis.

中文翻译：

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新型STAT3抑制剂STX-0119通过灭活小鼠的肝星状细胞来减轻肝纤维化。

肝纤维化的特征是在肝脏中形成疤痕组织。STAT3信号转导的作用与肝纤维化中活化肝星状细胞（HSC）成肌纤维母细胞样细胞有关。激活STAT3信号转导的主要因素是TGF-β1和IL-6，它们在患有肝纤维化的患者的肝脏中被上调。最近的报道表明，不仅IL-6而且TGF-β1的非经典信号传导途径也与STAT3信号传导相关。在这项研究中，我们证明了STAT3抑制剂STX-0119在肝纤维化中的新功能。STX-0119是STAT3二聚化抑制剂，是STAT3核定位所必需的。我们首先在体外实验中研究了STX-0119的抗纤维化作用。暴露于STX-0119会抑制HSC中STAT3的核定位，导致其靶基因（例如col1a1和αSMA）的表达下降。此外，STX-0119还抑制了TGF-β1/ IL-6诱导的HSC活化。接下来，我们使用硫代乙酰胺（TAA）和四氯化碳（CCl4）检查了STX-0119在肝纤维化小鼠模型中的体内作用。STX-0119通过抑制HSCs向成肌纤维细胞样细胞的活化来减轻TAA诱导的肝纤维化。与使用TAA诱导的肝纤维化模型的体内结果一致，STX-0119的治疗同样减弱了CCl4诱导的肝纤维化。总之，我们认为STX-0119通过阻止肝星状细胞的活化来抑制肝纤维化的发展。这些结果表明STX-0119是预防疾病发展为肝硬化的潜在新治疗策略。