延胡索酸水合酶（FH）在部分肾癌中发生失活突变，突变的肿瘤具有高度侵袭性且患者预后不佳。FH失活导致致癌代谢物-延胡索酸积累。目前认为延胡索酸共价修饰（琥珀酸酯化）E3泛素连接酶Keap1使其失活是主要的致癌机制。mTORC2-AKT信号通路异常激活是肿瘤恶性转化的普遍事件。前期工作中，我们通过BioID技术鉴定到mTORC2复合体成分mLST8是Keap1的互作蛋白。Keap1通过介导mLST8的非降解型泛素化修饰，抑制mTORC2复合体组装及下游AKT信号激活。本项目拟在分子、细胞、模式动物和病理样本水平研究延胡索酸累积通过抑制Keap1，激活mTORC2-AKT信号通路，促进FH突变型肾癌发生的机制及表型；并探讨mTOR/AKT抑制剂应用于FH突变型肾癌的靶向治疗策略。本项目将阐明“FH-延胡索酸-Keap1-mTORC2-AKT信号调节轴”，为FH突变肾癌的个性化治疗提供理论。

Fumarate hydratase (FH) is mutated in some kidney cancers, and the mutated tumors are highly invasive and the patient's prognosis is usually poor. FH inactivation leads to accumulation of the oncometabolite, fumarate. It is currently believed that fumarate covalently modifies E3 ubiquitin ligase Keap1 (succination) and makes its inactivation is a major carcinogenic mechanism. Abnormal activation of the mTORC2-AKT signaling pathway is a common event in malignant transformation of tumors. In the preliminary study, we identified the mTORC2 complex component mLST8 as the interaction protein of Keap1 through BioID methods. Keap1 inhibits mTORC2 complex assembly and downstream AKT signaling activation by mediating non-degradative ubiquitination of mLST8. This project intends to study the mechanism and phenotype of fumarate accumulation-induced Keap1 inactivation, mTORC2-AKT signaling pathway activation in FH mutant kidney cancer at the level of molecules, cells, model animals and pathological samples. We will explore the targeted therapeutic strategy of FH mutant kidney cancer using mTOR/AKT inhibitors. This project will clarify the "FH-fumarate-Keap1-mTORC2-AKT signal regulatory axis", providing a theoretical basis for the personalized treatment of FH mutant kidney cancer.