肝癌的发生发展与谷氨酰胺代谢异常改变密切相关，靶向谷氨酰胺代谢是抑制肝癌发生发展的重要方法之一。但肝癌谷氨酰胺代谢的调控机制还不明确。我们前期研究发现，m6A甲基转移酶WTAP在肝癌中高表达，通过介导m6A修饰调控细胞周期促进肝癌增殖。进一步研究发现，WTAP下游富集于谷氨酰胺代谢通路，且谷氨酰胺酶GLS的可变剪接与m6A修饰密切相关。我们拟在前期工作的基础上，从表观转录组学角度切入，采用体外肝癌细胞、条件性敲除WTAP小鼠、临床样本等研究体系，明确WTAP通过GLS可变剪接调控谷氨酰胺代谢促进肝癌发生发展的作用，阐明WTAP介导m6A修饰调控GLS可变剪接的分子机制，诠释WTAP在靶向谷氨酰胺代谢治疗肝癌中的临床价值。本项目的开展将揭示WTAP介导的m6A修饰调控谷氨酰胺代谢促进肝癌发生发展的机制，为WTAP作为肝癌治疗的潜在靶点做出进一步的探索。

The occurrence and development of hepatocellular carcinoma (HCC) is closely related to glutamine metabolic abnormalities. Although targeting glutamine metabolism is one of the most important methods to inhibit the tumorigenesis and development of HCC, its regulatory mechanism isn’t quite clear. Our previous research found that WTAP, an m6A methyltransferase, is highly expressed in HCC and promotes cancer cell proliferation by regulating cell cycle through m6A modification. Further experiments indicate that downstream targets of WTAP are enriched in the glutamine metabolic pathway, also, the alternative splicing of glutaminase (GLS) is bound up with m6A modification. Based on previous work, cutting in from a novel perspective of epitranscriptomics, we try to clarify the regulatory role of WTAP in HCC tumorigenesis through GLS alternative splicing in glutamine metabolism. Using research system as HCC cell lines, hepatic conditional knockout of WTAP mice and clinical samples, we hope to elucidate molecular mechanism of GLS alternative splicing regulated by WTAP-mediated m6A modification, furthermore, investigate the clinical value of WTAP in targeting glutamine metabolism to treat HCC. This project will reveal the mechanism of WTAP-mediated m6A modification in the occurrence and development of HCC by regulating glutamine metabolism, and make further exploration of WTAP as a potential target in HCC treatment.