Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction–associated steatohepatitis
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.
Authors
- Zhouxiang Wang
- Lan Bai (ORCID: https://orcid.org/0000-0002-8859-1540)
- Han Tian (ORCID: https://orcid.org/0000-0003-0218-7246)
- Jingwei Jiang (ORCID: https://orcid.org/0000-0001-6618-6993)
- Weiyi Qu (ORCID: https://orcid.org/0000-0002-8046-0140)
- Haibo Xu (ORCID: https://orcid.org/0000-0002-8451-8979)
- Ruifeng Tian (ORCID: https://orcid.org/0000-0003-2827-6941)
- Yu‐Feng Hu (ORCID: https://orcid.org/0000-0001-5715-2070)
- Zhi‐Gang She (ORCID: https://orcid.org/0000-0001-9402-4166)
- Hailong Yang (ORCID: https://orcid.org/0000-0002-0360-6492)
- Hongqiang Shen (ORCID: https://orcid.org/0000-0001-7188-5289)
- Liang Fang (ORCID: https://orcid.org/0000-0001-7809-5001)
- Rufang Liao
- Wei Li (ORCID: https://orcid.org/0000-0003-4143-8597)
- Xin Zhang (ORCID: https://orcid.org/0000-0003-4298-7926)
- Peng Zhang (ORCID: https://orcid.org/0000-0002-7468-6848)
- Tian Tian (ORCID: https://orcid.org/0000-0001-8895-755X)
- Xiao‐Jing Zhang (ORCID: https://orcid.org/0000-0002-8271-7405)
- Hongliang Li (ORCID: https://orcid.org/0000-0002-9821-0297)
- Kun Wang (ORCID: https://orcid.org/0000-0001-9851-7080)
- Yibin Wang (ORCID: https://orcid.org/0000-0003-0852-0767)
- Song Tian (ORCID: https://orcid.org/0000-0002-7006-6588)
- Junjie Zhou (ORCID: https://orcid.org/0000-0002-9588-9839)
- Jingjing Cai (ORCID: https://orcid.org/0000-0003-2466-754X)
- Jiajun Fu (ORCID: https://orcid.org/0000-0002-8542-9556)
- Hongfei Duan (ORCID: https://orcid.org/0000-0002-9400-6838)
- Juan Wan (ORCID: https://orcid.org/0000-0003-4869-2459)
- Jing Bo Shi (ORCID: https://orcid.org/0000-0002-9257-6060)
- Toujun Zou
- Xu Cheng (ORCID: https://orcid.org/0000-0002-3003-5971)
Institutions
- Central South University (CN)
- China Pharmaceutical University (CN)
- University of Macau (MO)
- Wuhan University (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Duke-NUS Medical School (SG)
- First Affiliated Hospital of Gannan Medical University (CN)
- Renmin Hospital of Wuhan University (CN)
- Third Xiangya Hospital (CN)
- Huanggang Central Hospital (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-09-02
- DOI
- https://doi.org/10.1172/jci173193
- Citations
- 6
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 8.13
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Hubei Province
- Wuhan University
- Zhongnan Hospital of Wuhan University
- National Science and Technology Major Project