ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
GPER1 as a therapeutic target in MASLD: Evidence for steatosis attenuation by agonist G1 in preclinical models
Yifang Li
Jian Jiao
China-Japan Union Hospital, Jilin University, Changchun, China
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Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver-related morbidity and mortality. Premenopausal women have a lower MASLD risk than postmenopausal women. G protein-coupled estrogen receptor 1 (GPER1) exerts hepatic protective effects, and GPER1 specific agonist (G1) has shown preclinical potential in improving metabolic disorders. However, clinical studies on G1's metabolic benefits and GPER1's clinical relevance in human liver tissue remain unclear. This study aims to bridge basic and clinical research by validating G1's efficacy in ameliorating MASLD-related hepatic steatosis, exploring its molecular mechanisms, and clarifying GPER1's association with human MASLD. Methods We investigated the expression of GPER1 in human liver tissue and its correlation with the severity of steatosis. The function of GPER1 was validated both in vitro (using a free fatty acid-induced hepatocyte steatosis model treated with the GPER1 agonist G1 or antagonist G15) and in vivo, with assessments of lipid metabolism-related genes, reactive oxygen species, and apoptosis. GPER1-associated proteins were identified through proteomic sequencing and co-immunoprecipitation. Results GPER1 is lowly expressed in MASLD patients, negatively correlating with steatosis severity. G1 upregulates GPER1, alleviates hepatocyte steatosis and lipid deposition, modulates lipid metabolism-related proteins, ameliorates hepatic steatosis, and interacts with GAIP-interacting protein C-terminal 1 (GIPC1). G15 antagonizes these beneficial effects. Conclusions Based on clinical data, this study shows that low GPER1 expression correlates closely with hepatic steatosis in MASLD. The GPER1 agonist G1 ameliorates hepatic steatosis via multiple GPER1-dependent mechanisms, including regulating lipid metabolism, suppressing oxidative stress, and reducing apoptosis. Notably, GIPC1 may be involved in the GPER1-mediated regulatory pathway, and its role in this context merits further investigation.
Summary
Keywords
G protein-coupledestrogen receptor 1 (GPER1), GPER1 antagonist (G15), GPER1-specific agonist (G1), Hepatic Steatosis, Metabolic dysfunction-associated steatotic liverdisease (MASLD)
Received
09 December 2025
Accepted
20 February 2026
Copyright
© 2026 Li and Jiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jian Jiao
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