疏肝健脾活血方双向调控TGFβ1-CUGBP1/IFNγ-Smad7通路抑制HSCs活化的抗肝纤维化机制

肝纤维化是各种慢性肝病发展为肝硬化、甚至肝癌的共同必经阶段，HSCs活化是肝纤维化发生发展的中心环节。研究发现，促肝纤维化的TGF-β1/CUGBP1通路和抗肝纤维化的IFN-γ/Smad7通路间失衡能诱导HSCs活化，是导致肝纤维化发生的关键。课题组前期研究发现，疏肝健脾活血方能降低肝纤维化大鼠肝组织TGF-β1，增强Smad7对TGF-β1的负反馈作用，抑制活化的HSCs中CUGBP1，促进IFN-γ的表达，提出疏肝健脾活血方通过调控CUGBP1介导的TGF-β1和IFN-γ通路之间的相互作用，抑制TGF-β1/CUGBP1，激活IFN-γ/Smad7通路，发挥抗肝纤维化作用的假说。本项目通过构建腺相关病毒、质粒转染及RNA干扰等技术深入探讨疏肝健脾活血方对TGFβ1-CUGBP1-IFNγ-Smad7转导环路的作用环节，为以调控HSCs活化和稳态为靶点的肝纤维化治疗提供实验依据。

Hepatic fibrosis is a common stage for various chronic liver diseases to develop into cirrhosis and even hepatocellular carcinoma. Activation of HSCs is the central link in the development of hepatic fibrosis. It was found that the imbalance between TGF-β1/CUGBP1 pathway promoting hepatic fibrosis and IFN-γ/Smad7 pathway inhibiting hepatic fibrosis can induce HSCs activation, which is the key to hepatic fibrosis. Previous studies have found that Shugan Jianpi Huoxue Recipe can reduce TGF-β1 in liver tissue of rats with liver fibrosis, enhance the negative feedback effect of Smad7 on TGF-β1, inhibit the expression of CUGBP1 in activated HSCs, and promote the expression of IFN-γ. It is proposed that Shugan Jianpi Huoxue Recipe can inhibit the interaction between TGF-β1 and IFN-γ pathways mediated by CUGBP1, inhibit TGF-β1/CUGBP1, and activate IFN-γ/Smad7 pathway. In this project, adeno-associated virus construction, plasmid transfection and RNA interference techniques are used to explore the role of Shugan Jianpi Huoxue recipe in the transduction loop of TGF-β1-CUGBP1-IFNγ-Smad7, and to provide experimental basis for the treatment of liver fibrosis targeting at regulating the activation and homeostasis of HSCs.