基于中医药理论结合现代生物学技术探索肝癌索拉非尼耐药（HSR）的分子机制及干预药物是寻找逆转耐药治疗策略的关键。Hippo信号通路被发现与肝癌的增殖、侵袭转移及干细胞特性的维持密切相关。然而，该通路是否参与HSR过程还不得而知。我们前期研究发现，Hippo信号通路在HSR细胞中活性增强，且与用药患者的反应性和预后相关，而中药芫花提取物芫花烯则可抑制Hippo信号通路，并能逆转HSR。然而，对于Hippo信号通路在HSR过程中的角色和以芫花烯分子靶向调控该通路的确切机制和治疗意义等问题还亟待阐明。为此，本课题拟采用多种分子生物学方法：1）进一步探索Hippo通路在HSR过程中的角色地位，为靶向逆转HSR策略提供明确的切入点和靶标。2）深入探究芫花烯靶向调控此信号通路的分子机制，并阐明其逆转HSR的作用特点，从而为丰富中药芫花的药用内涵，并将芫花烯开发为新型逆转HSR的药物奠定药理学基础。

Based on the Chinese medicine theory combined with modern biological technology, exploring the molecular mechanism of hepatocellular carcinoma sorafenib resistance (HSR) and finding drug intervention is the key to reverse the drug-based treatment strategies. Hippo signaling pathway was reported to relate to the proliferation and invasion of hepatocellular carcinoma, as well as stem cell characteristics. However, whether Hippo pathway is involved in HSR process is still unknown. In our preliminary study, we found Hippo signaling pathway activity was increased in HSR cells, and predicted the patient's treatment response and prognosis. Meanwhile, the traditional Chinese medicine extract, Genkwadaphnine, was found not only can suppress Hippo signaling pathway but also reverse the HSR. However, it is need to clarify the role of Hippo signaling pathway in HSR, and the underlying mechanisms of Genkwadaphnine targeting Hippo signaling and therapeutic value of Genkwadaphnine on HSR also need to further be illustrated. Therefore, using multiple molecular biology methods, we plan to: 1)to further explore the role of Hippo pathway in HSR process, providing a clear target for reversing HSR; 2) to investigate the underlying regulation mechanisms of Genkwadaphnine on Hippo signaling pathway and clarify its characteristic of reversing HSR, which will enrich the connotation of Traditional Chinese Medicine Daphne genkwa and establish the pharmacological basis for developing Genkwadaphnine as a new drug of reversing HSR.