索拉非尼是目前晚期肝癌最常用的一线靶向用药，但其疗效不佳，大部分患者对索拉非尼耐药。我们前期工作提示：索拉非尼耐药肝癌细胞中SH3GLB1表达升高促进了耐药；其中，我们发现SH3GLB1介导的线粒体自噬，可以激活Nrf2-Keap1，促进肿瘤细胞干细胞样特征，介导索拉非尼耐药。在此我们提出假说：SH3GLB1通过Nrf2-Keap1调控肝癌干细胞样特征介导索拉非尼耐药。围绕这一假说，本课题组将运用质谱分析、染色质免疫共沉淀等方法，从体外、体内和临床组织样本三方面1）进一步明确SH3GLB1介导肝癌对索拉非尼耐药；2）揭示SH3GLB1对Nrf2-Keap1信号通路的具体调控机制；3）探索SH3GLB1及相关信号分子作为耐药预测指标和治疗靶点的可行性。本课题的开展为阐明肝癌细胞耐药新机制和耐药新靶向治疗提供依据，具有良好的临床应用价值。

Nowadays, sorafenib is the most frequently used first-line agent for advanced hepatocellular carcinoma(HCC) patience. However, most of the patient acquired resistance to sorafenib. One main reason is the mechanism of resistance to sorafenib remains unknown.In our previously study, our study demonstrated that SH3GLB1 may participate in sorafenib resistance and could enhance the efficacy of sorafenib treatment. Moreover,the activities of SH3GLB1/Nrf2/Keap1 axis lead to mitophagy enhanced and positively regulates cancer stem characteristics of HCC cells, and confers resistance to sorafenib. Thus, we hypothesized thatSH3GLB1/Nrf2/Keap1 axis may promote resistance to sorafenib by regulates cancerstem characteristics of HCC cells.To identify this scientific hypothesis, we willutilize mass spectrometric analysis, chromatin immunoprecipitation and other methods to determine that SH3GLB1 is a novel target which are involved in resistance of sorafenib on the basis of in vitro, in vivo and clinical tissue examples. Futuremore, we will examine the impact of SH3GLB1 activation on the regulation of Nrf2-Keap1, and explore the feasibility of SH3GLB1 and thedownstream molecules as the prognostic factor and potential therapeutic target for HCC. The present study will address a new mechanism for acquired resistance tochemotherapy and provide new ideas to therapeutic target for HCC.