Comprehensive Liver Cancer Centre, the Fifth Medical Center of PLA General Hospital, Beijing, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Cell Death Dis. 2020 Feb 12;11(2):118. doi: 10.1038/s41419-020-2229-2.
Recent studies suggest that Src family kinase (SFK) plays important roles in systemic sclerosis and pulmonary fibrosis. However, how SFKs contributed to the pathogenesis of liver fibrosis remains largely unknown. Here, we investigated the role of Fyn, a member of SFK, in hepatic stellate cell (HSC) activation and liver fibrosis, and evaluated the anti-fibrotic effects of Saracatinib, a clinically proven safe Fyn inhibitor. Fyn activation was examined in human normal and fibrotic liver tissues. The roles of Fyn in HSC activation and liver fibrosis were evaluated in HSC cell lines by using Fyn siRNA and in Fyn knockout mice. The effects of Saracatinib on HSC activation and liver fibrosis were determined in primary HSCs and CCl induced liver fibrosis model. We showed that the Fyn was activated in the liver of human fibrosis patients. TGF-β induced the activation of Fyn in HSC cell lines. Knockdown of Fyn significantly blocked HSC activation, proliferation, and migration. Fyn deficient mice were resistant to CCl induced liver fibrosis. Saracatinib treatment abolished the activation of Fyn, downregulated the Fyn/FAK/N-WASP signaling in HSCs, and subsequently prevented the activation of HSCs. Saracatinib treatment significantly reduced the severity liver fibrosis induced by CCl in mice. In conclusions, our findings supported the critical role of Fyn in HSC activation and development of liver fibrosis. Fyn could serve as a promising drug target for liver fibrosis treatment. Fyn inhibitor Saracatinib significantly inhibited HSC activation and attenuated liver fibrosis in mouse model.
最近的研究表明，Src 家族激酶（SFK）在系统性硬化症和肺纤维化中发挥重要作用。然而，SFKs 如何促进肝纤维化的发病机制在很大程度上仍然未知。在这里，我们研究了 Fyn（SFK 的一个成员）在肝星状细胞（HSC）活化和肝纤维化中的作用，并评估了 Saracatinib（一种临床证明安全的 Fyn 抑制剂）的抗纤维化作用。检查了人正常和纤维化肝组织中 Fyn 的激活情况。通过使用 Fyn siRNA 在 HSC 细胞系中以及在 Fyn 敲除小鼠中评估了 Fyn 在 HSC 活化和肝纤维化中的作用。在原代 HSCs 和 CCl 诱导的肝纤维化模型中，确定了 Saracatinib 对 HSC 活化和肝纤维化的影响。我们表明 Fyn 在纤维化患者的肝脏中被激活。TGF-β诱导 HSC 细胞系中 Fyn 的激活。Fyn 敲低显着阻断 HSC 活化、增殖和迁移。Fyn 缺陷小鼠对 CCl 诱导的肝纤维化具有抗性。Saracatinib 治疗消除了 Fyn 的激活，下调了 HSCs 中的 Fyn/FAK/N-WASP 信号通路，随后阻止了 HSCs 的激活。Saracatinib 治疗显着降低了 CCl 在小鼠中诱导的肝纤维化的严重程度。总之，我们的研究结果支持 Fyn 在 HSC 活化和肝纤维化发展中的关键作用。Fyn 可作为肝纤维化治疗的有前途的药物靶点。Fyn 抑制剂 Saracatinib 显着抑制 HSC 活化并减轻小鼠模型中的肝纤维化。
