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Here, we performed an integrated multilayered screening for pathogenic genes and druggable targets for MASH. We identified the subclass of metabolite-sensing G protein\u2013coupled receptors, specifically GPR31, a critical contributor to MASH occurrence, which, to our knowledge, was previously uncharacterized. Mechanistically, G\u03b1i3 is the essential downstream effector for the pro-MASH efficiency of GPR31 via glycosylation-dependent interaction with GPR31 and extra activation of PKC\u03b4-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-G\u03b1i3 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.<\/jats:p>","DOI":"10.1172\/jci173193","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T16:12:16Z","timestamp":1756829536000},"source":"Crossref","is-referenced-by-count":7,"title":["Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction\u2013associated steatohepatitis"],"prefix":"10.1172","volume":"135","author":[{"given":"Xiao-Jing","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, China."},{"name":"Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 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