脂质代谢重塑在结直肠癌变中起重要作用，研究其机制对结直肠癌防治有重要意义。我们发现：苹果酸酶ME1 S336磷酸化和K337乙酰化的动态调控影响ME1多聚化和活性;USP19去泛素化和稳定ME1增加脂肪酸合成、NADPH产生和降低活性氧(ROS)；ROS增强NRF2而激活PD-L1表达；小鼠Usp19缺失衰减脂质代谢、NADPH产生和结直肠癌变；ERK2磷酸化ME1苏氨酸而稳定ME1；抑制ERK2或ME1增加PD-L1表达导致结直肠癌免疫逃逸。肠癌患者增加的ERK2、USP19-ME1活性和脂质合成与结直肠癌变密切相关。本项目将研究USP19去泛素化ME1的关键位点和其生物学效应；ME1是否介导USP19促进代谢和癌变表型；ERK2磷酸化ME1稳定ME1蛋白和重塑脂质代谢的机制；结合靶向ERK2和PD-L1治疗结直肠癌的效果。将利于揭示结直肠癌脂质代谢重塑的机制，为结直肠癌防治提供新思路。

Lipid metabolism reprogramming plays important roles in colorectal carcinogenesis and it is of great significance to study its specific detail mechanism for the prevention and treatment of colorectal cancer. We found that the dynamic regulation of ME1 S336 phosphorylation and K337 acetylation affects ME1 aggregation and activation; ME1 is shown to interact with USP19 by protein co-immunoprecipitation and USP19 deubiquitinates and stabilizes ME1 to promote fatty acid synthesis and NADPH production and reduce reactive oxygen species (ROS) level; ROS enhances NRF2 expression and increases PD-L1 expression; Usp19 deletion attenuates lipid metabolism, NADPH production and colorectal carcinogenesis in mice; Activated ERK2 in colorectal cancer phosphorylates ME1 threonine and stabilizes its protein; Inhibiting ERK2 or ME1 increases PD-L1 expression and causes immune escape of colorectal cancer; The increased activity of ERK2, USP19-ME1 and lipid synthesis in human patients with colorectal cancer are closely related to colorectal carcinogenesis. This project will study the key sites and biological effects of USP19 deubiquitinating ME1; Study whether ME1 mediates USP19 metabolism and oncogenic phenotypes; Explore the mechanisms of ERK2-mediated ME1 phosphorylation causing ME1 protein stabilization and lipid metabolism reprogramming; Study the effects of combination of targeting ERK2 and PD-L1 in the treatment of colorectal cancer. It will help to reveal the mechanisms of lipid metabolism reprogramming in colorectal cancer, and provide new ideas for the prevention and treatment of colorectal cancer.