孤儿受体GPR35通过代谢重编程调控巨噬细胞极化发挥抗药物性肝损伤作用

巨噬细胞在药物性肝损伤中扮演核心角色，抑制其炎性极化是治疗此疾病的重要思路。目前对调控巨噬细胞极化的潜在靶点及调控机制仍不清楚。我们近期发现，药物性肝损伤导致巨噬细胞上调GPR35；敲除GPR35导致炎症因子升高且肝损伤加重；机制研究显示抑制葡萄糖6-磷酸脱氢酶可逆转GPR35缺失导致的肝损伤加重。据此我们推测：GPR35可通过代谢重编程抑制巨噬细胞炎性极化发挥抗药物性肝损伤的作用。本课题拟首先分析药物性肝损伤过程中GPR35在肝巨噬细胞上的动力学变化；然后通过基因敲除、药物处理、转录组学及代谢组学分析等确定GPR35对巨噬细胞极化、代谢重编程及药物性肝损伤的调控作用，并深入探究GPR35代谢调控巨噬细胞极化的机制；最后验证GPR35在药物性肝损伤临床组织样本中的表达及其对人巨噬细胞炎性极化及代谢的调控作用。本课题将阐明GPR35对药物性肝损伤的保护作用及机制，为药物性肝病防治提供新靶点。

Macrophages play a central role in drug-induced liver injury. The inhibition of macrophage inflammatory polarization is an important idea for the disease treatment. However, the potential targets and mechanisms of regulating macrophage polarization remain unclear. We have recently discovered that GPR35 expression was up-regulated on macrophages during drug-induced liver injury. The knockout of GPR35 resulted in increased inflammatory factors and worsened liver damage. The investigation on mechanisms showed that inhibition of glucose 6-phosphate dehydrogenase could reverse liver damage caused by GPR35 deficiency. Based on the findings, we hypothesized that GPR35 protects against drug-induced liver injury by regulating macrophage polarization through metabolic reprogramming. This project aims to firstly analyze the dynamic changes of GPR35 on hepatic macrophages during drug-induced liver injury; then, through gene knockout, cell-specific knockout, drug treatment, transcriptomics, and metabolomics analysis, we will determine the regulatory effects of GPR35 on macrophage polarization, metabolic reprogramming, and drug-induced liver injury, and further explore the mechanism by which GPR35 metabolically regulates macrophage polarization; and finally we will verify the expression of GPR35 in clinical tissue samples of drug-induced liver injury and their regulatory effects on inflammatory polarization and metabolism of human macrophages. The implementation of this project will clarify the protective effect and mechanism of GPR35 on drug-induced liver injury, and provide new targets for the prevention and treatment of drug-induced liver disease.