Zhao Xueqin, Li Yuanhao, Yang Liu, Chen Xi, Zhang Jialong, Chen Tong, Wang Haoqi, Li Fei, Cheng Chen, Wu Jingjing, Cong Jingjing, Yin Wenwei, Li Jing, Wang Xuefu
School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, #81 Meishan Road, Hefei, 230032, Anhui, China.
School of Life Sciences, Anhui Medical University, #81 Meishan Road, Hefei, 230032, Anhui, China.
Cell Mol Life Sci. 2025 May 29;82(1):219. doi: 10.1007/s00018-025-05751-4.
Acetaminophen (APAP) overdose induces acute liver injury and represents the most frequent cause of drug-induced liver injury worldwide. Macrophage-mediated inflammation plays detrimental roles during the early stage of liver injury. However, the potential targets regulating inflammation to improve drug-induced liver injury remains undefined. In this study, we reported that G protein-coupled receptor 35 (GPR35) improves drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cyclic AMP-protein kinase A (Gαs-cAMP-PKA) pathway. The ablation of GPR35 exacerbates APAP-induced liver injury, characterized by higher levels of alanine aminotransferase and aspartate aminotransferase in sera, larger damaged areas, and increased levels of pro-inflammatory cytokines. More hepatic macrophages appeared in the inflamed liver of mice with GPR35 deficiency. In contrast, the agonists of GPR35 alleviated APAP-induced liver injury. The depletion of macrophages abolished GPR35-mediated protection. Mechanistically, GPR35 ablation facilitated the activation of pro-inflammatory AKT, MAPK, and NF-κB signaling pathways at the downstream of Toll-like receptors in macrophages. GPR35 agonists activated Gαs-cAMP-PKA signaling to inhibit the activation of these pro-inflammatory signaling pathways and then suppress the inflammatory response in macrophages. Thus, our findings demonstrate that GPR35 prevents drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cAMP-PKA pathway, indicating that GPR35 is a potential target for the development of novel medicines that control drug-induced liver injury.
对乙酰氨基酚（APAP）过量会引发急性肝损伤，是全球范围内药物性肝损伤最常见的原因。巨噬细胞介导的炎症在肝损伤早期发挥着有害作用。然而，调节炎症以改善药物性肝损伤的潜在靶点仍不明确。在本研究中，我们报告称G蛋白偶联受体35（GPR35）通过Gαs - 环磷酸腺苷 - 蛋白激酶A（Gαs - cAMP - PKA）途径阻断巨噬细胞介导的炎症来改善药物性肝损伤。GPR35基因敲除会加剧APAP诱导的肝损伤，其特征为血清中丙氨酸转氨酶和天冬氨酸转氨酶水平升高、受损面积增大以及促炎细胞因子水平增加。在GPR35缺陷小鼠的炎症肝脏中出现了更多的肝巨噬细胞。相反，GPR35激动剂减轻了APAP诱导的肝损伤。巨噬细胞的清除消除了GPR35介导的保护作用。从机制上讲，GPR35基因敲除促进了巨噬细胞中Toll样受体下游促炎AKT、MAPK和NF - κB信号通路的激活。GPR35激动剂激活Gαs - cAMP - PKA信号以抑制这些促炎信号通路的激活，进而抑制巨噬细胞中的炎症反应。因此，我们的研究结果表明，GPR35通过Gαs - cAMP - PKA途径阻断巨噬细胞介导的炎症来预防药物性肝损伤，这表明GPR35是开发控制药物性肝损伤新药的潜在靶点。
