A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice
A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice
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DOI：
10.1016/j.bbrc.2019.03.156
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发表时间：
2019-05-21
影响因子：
3.1
通讯作者：
Oh, Seung Hyun
中科院分区：
文献类型：
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作者：
Choi, Seungho;Jung, Hyun Jin;Oh, Seung Hyun
肝纤维化的特征是在肝脏中形成瘢痕组织。在肝纤维化中，STAT 3信号传导的作用涉及将肝星状细胞（HSC）活化为肌纤维母细胞样细胞。激活STAT 3信号传导的主要因素是TGF-β 1和IL-6，它们在患有肝纤维化的患者的肝脏中上调。最近的报道表明，不仅IL-6，而且TGF-β 1的非经典信号传导途径与STAT 3信号传导相关。在这项研究中，我们证明了STAT 3抑制剂STX-0119在肝纤维化中的新功能。STX-0119是STAT 3二聚化的抑制剂，其是STAT 3的核定位所需的。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抑制了HSC 5中STAT 3的核定位，导致其靶基因如胶原和α SMA的表达降低。此外，STX-0119还抑制TGF-β 1/1-6诱导的HSC活化。接下来，我们使用硫代乙酰胺（TAA）和四氯化碳（CCL 4）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HSC 5活化为肌纤维母细胞样细胞来减轻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的治疗类似地减弱了CCl 4诱导的肝纤维化。总之，我们认为STX-0119通过阻断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是一种潜在的新的治疗策略，以防止疾病进展为肝硬化。(C)2019爱思唯尔公司All rights reserved.
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-beta 1 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-beta 1 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 HSC5, resulting in decreased expression of its target genes, such as collal and alpha SMA. In addition, STX-0119 also inhibited the TGF-beta 1/1-6-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 HSC5 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. (C) 2019 Elsevier Inc. All rights reserved.