TGF-β信号在肝纤维化及肝癌的发生发展过程中起关键作用，但其作为药物靶标却缺少合适的切入点。我们的前期研究发现了肝星状细胞中促纤维化TGF-β信号和抗纤维化IFN-γ信号之间的关键链接分子CUGBP1。本项目拟通过靶向抑制CUGBP1及其与靶基因的相互作用，增强内源性抗纤维化信号，确立恢复肝纤维化制衡的新方法。包括：确证CUGBP1具有调控多种抗纤维化信号的关键节点样作用，探讨其与肝纤维化进展与转归的关联；建立基于CUGBP1及其与靶基因相互作用的活性评价及多层次的药物筛选体系；借助遗传操纵法、各种信号通路抑制剂及现有抗纤维化药物等证实其药物靶标属性；在此基础上发现先导化合物、探讨其化学特征和作用特点，经结构优化获得潜在的候选药物；系统探讨选定的化合物靶向CUGBP1及其与靶基因的相互作用与恢复肝星状细胞稳态、抗肝纤维化和抗肝癌活性的相关性，为新型抗肝纤维化和抗肝癌药物的研制奠定基础。

TGF-β signaling plays a key role in the pathogenesis of liver fibrosis and hepatocarcinoma. However, there is still lack of an ideal molecule as a drug target. Our previous study found a key molecule CUGBP1 as a link between the profibrotic TGF-β and anti-fibrotic IFN-γ signaling pathways in hepatic satellite cells (HSCs). On the basis of this result, this study aims at establishing a novel approach to the recovery from liver fibrosis via targeting CUGBP1 and its interaction with the target genes. We will confirm the key molecule effect of CUGBP1 that controls some anti-fibrotic signals, and evaluate its relation to the progress of and recovery from the liver fibrosis. We will establish a series of assays for targeting CUGBP1 and its interaction with the target genes. Then, we will verify the drug target property by means of genetic approaches, inhibitors of various signal pathways, and current anti-fibrotic drugs. Based on these findings, we will search for a lead compound with its chemical and biological features and a potential drug candidate after structural optimization. Then, examination will be performed on the relation of the anti-CUGBP1 activity of the selected compound to the homeostasis of HSCs, as well as to the anti-liver fibrotic and anti-hepatocarcinoma effects. This study will lay the foundation for the new drug development against liver fibrosis and hepatocarcinoma.