Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction–associated steatohepatitis

作者：Xiao‐Jing Zhang, Jiajun Fu, Xu Cheng, Hongqiang Shen, Hailong Yang, Kun Wang, Wei Li, Han Tian, Tian Tian, Junjie Zhou, Song Tian, Zhouxiang Wang, Juan Wan, Lan Bai, Hongfei Duan, Xin Zhang, Ruifeng Tian, Haibo Xu, Rufang Liao, Toujun Zou, Jing Bo Shi, Weiyi Qu, Liang Fang, Jingjing Cai, Peng Zhang, Zhi‐Gang She, Jingwei Jiang, Yu‐Feng Hu, Yibin Wang, Hongliang Li · 发表于：Journal of Clinical Investigation · 年份：2025 · DOI：10.1172/jci173193 · 被引用次数：7 · 研究领域：Liver Disease Diagnosis and Treatment、Diet, Metabolism, and Disease、Pancreatic function and diabetes

Metabolic dysfunction-associated steatohepatitis (MASH) is a globally prevalent but intractable disease lacking effective pharmacotherapies. Here, we performed an integrated multilayered screening for pathogenic genes and druggable targets for MASH. We identified the subclass of metabolite-sensing G protein-coupled receptors, specifically GPR31, a critical contributor to MASH occurrence, which, to our knowledge, was previously uncharacterized. Mechanistically, Gαi3 is the essential downstream effector for the pro-MASH efficiency of GPR31 via glycosylation-dependent interaction with GPR31 and extra activation of PKCδ-MAPK signaling. Hepatocyte-specific GPR31 deficiency robustly blocked hepatic lipotoxicity and fibrosis in a mouse model of diet-induced MASH, whereas expression of the GPR31 transgene aggravated MASH development. Of translational importance, we developed a small-molecule inhibitor, named G4451, that specifically inhibits the GPR31-Gαi3 interaction by targeting the GPR31 conformational transition. Encouragingly, oral administration of G4451 effectively blocked MASH progression in preclinical models in both rodents and nonhuman primates. Collectively, the present study provides proof of concept that interference with GPR31 constitutes an attractive therapeutic strategy for MASH.