代谢异常是近年来肿瘤研究热点，研究已证实代谢物异常累积促进肿瘤的复发转移。癌代谢物延胡索酸（fumarate）加速肿瘤恶性进展，但对肝癌复发转移的作用及机制尚未明确。我们前期研究发现延胡索酸异常累积加剧肝癌的复发和转移，并增强肿瘤干性表型，且肝癌患者延胡索酸酶（fumarate hydratase，FH）与肿瘤干性标志物呈负相关。据此我们假设肝癌FH下降导致延胡索酸异常蓄积可能通过调控肿瘤干性的重编程，进而促进肝癌复发转移。为验证该假设，我们将干预FH观察其对复发转移的影响；利用RNA-seq、质谱和蛋白芯片等技术揭示延胡索酸调控肝肿瘤干性表型的关键分子；通过表观遗传学研究阐明延胡索酸调控甲基化修饰进而维持干性表型的机制。本项目从肿瘤代谢入手，在细胞、动物及组织学水平研究延胡索酸对肿瘤干性表型的调控作用，并阐明其对肿瘤干性重编程的调控机制，为防治肝癌转移复发的代谢干预提供新思路及干预靶点。

Metabolic abnormalities during tumorigenesis and development are hotspots in recent years. Metabolite accumulation has been linked to the relapse and metastasis in various cancers. The oncometabolite fumarate was reported to promote tumor progression, but its underlying molecular mechanism in HCC remains unclear. Our previous study found that abnormal accumulation of fumarate aggravated the recurrence and metastasis and increased stemness features of HCC, and that the expression level of fumarate hydratase (FH) was inversely correlated with that of biomarkers of cancer stem cells. Thus, we hypothesize that the accumulated fumarate derived from the downregulation of FH facilitates poor prognosis via reprogramming of cancer stemness. To confirm this assumption, we will silence FH expression to investigate its impact on tumor recurrence and metastasis, reveal the key molecule regulating cancer stemness by using RNA-seq, LC-MS, and Phospho Explorer Assays, and clarify the intrinsic mechanism that fumarate regulates methylation to reprogram the cancer stemness features. In the present project, we will perform in vivo and in vitro experiments to study the effects of oncometabolite fumarate on stemness features of HCC, illustrate the underlying mechanism of fumarate on the reprogramming of cancer stemness via epigenetics. Our finds will provide a novel insight into the prevention and treatment of HCC.