HBV感染诱导氧化应激(OS)激活肝星状细胞(HSC)是肝纤维化形成的病因之一。GSK3β/Nrf2通路参与了肝细胞损伤的调控，但该通路是否参与HBV感染患者HSC活化增殖的调节，机制不清，亟待突破。前期研究发现，HCV感染患者肝纤维化程度与磷酸化GSK3β和Nrf2蛋白水平呈负相关。本项目提出新假说，GSK3β通过调控Nrf2的活性，影响HSC活化增殖，从而参与肝纤维化的调节。拟在肝组织水平、HSC细胞模型和肝纤维化动物模型水平分别进行GSK3β通过调节Nrf2活性对HSC影响机制的研究，HBV感染诱导OS抑制GSK3β活性，上调Nrf2表达，促进HSC凋亡和细胞外基质的产生。试图揭示GSK3β磷酸化/Nrf2抗氧化增强/HSC活化抑制的通路，探清GSK3β/Nrf2通路参与HBV感染患者HSC活化增殖调节的功能和机制，为抗肝纤维化治疗提供可能新的靶点。

Activation of hepatic stellate cells (HSCs) has been recognized as one of the leading causes of liver fibrosis. There are many factors contributing to HSC activation, and an outstanding one among these is Hepatitis B virus (HBV) infection-induced oxidative stress (OS). It is believed that Glycogen synthase kinase 3β (GSK3β)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway plays a role in the regulation of hepatocellular damage. In addition, previous studies revealed that the severity of liver fibrosis is negatively correlated to the levels of GSK3β and Nrf2. However, it remains elucidated whether GSK3β/Nrf2 signaling pathway regulates the activation and proliferation of HSCs during chronic HBV infection. Given the facts above, we hypothesize that GSK3β serves as an upstream regulator of liver fibrosis by manipulating the activity of Nrf2 which subsequently controls the activation and proliferation of HSCs. To better understand the mechanisms via which HBV infection-induced OS suppresses the activity of GSK3β, upregulates the expression of Nrf2 and facilitates the apoptosis of HSCs as well as the generation of extracellular matrix at different levels, we will apply liver tissues, immortalized hepatic cell lines and liver fibrotic animal models in our study. On top of this, the study is aimed at identifying a novel pathway: phosphorylation of GSK3β/enhancement of Nrf2 anti-oxidation/suppression of HSC activation, which potentially provides new perspectives and targets regarding anti-liver fibrosis therapy.