GPR35 prevents drug-induced liver injury via the Gαs-cAMP-PKA axis in macrophages

作者：Xueqin Zhao, Y Li, Liu Yang, Xi Chen, Jialong Zhang, Tong Chen, Hao‐Qi Wang, Fei Li, Cheng Chen, Jingjing Wu, Jingjing Cong, Wenwei Yin, Jing Li, Xuefu Wang · 发表于：Cellular and Molecular Life Sciences · 年份：2025 · DOI：10.1007/s00018-025-05751-4 · 被引用次数：8 · 研究领域：Drug Transport and Resistance Mechanisms、Diabetes Treatment and Management、Neuropeptides and Animal Physiology

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 t...