MHY5456, an FXR Agonist, Ameliorates Hepatic Steatosis and Fibrosis in a Mouse Model of MASLD
10.4062/biomolther.2025.256
- Author:
Mi-Jeong KIM
1
;
Hyejin KANG
;
Jian YOO
;
Sugyeong HA
;
Jeongwon KIM
;
Byeong Moo KIM
;
Da Eun PARK
;
Hae Young CHUNG
;
Donghwan KIM
;
Hyung Ryong MOON
;
Ki Wung CHUNG
Author Information
1. College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2026;34(3):652-665
- CountryRepublic of Korea
- Language:English
-
Abstract:
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global health issue due to its increasing prevalence associated with lifestyle changes and its strong correlation with metabolic syndrome. Farnesoid X receptor (FXR) is a nuclear receptor that plays a pivotal role in regulating bile acid, lipid, and glucose metabolism, making it an attractive therapeutic target for liver and metabolic diseases. In this study, we investigated the effects of MHY5456, a synthetic agonist of FXR, on hepatic metabolism and fibrosis. MHY5456 enhanced the transcriptional activity of FXR in a concentration-dependent manner.Treatment of AC2F rat liver-derived cells with MHY5456 resulted in the downregulation of genes involved in lipid accumulation and an upregulation of mitochondrial-related gene expression. Additionally, MHY5456 significantly reduced oleic acid (OA)-induced lipid accumulation. To assess its anti-fibrotic potential, we tested its effects on transforming growth factor-beta (TGF-β)-induced fibrosis in LX2 human hepatic stellate cells (HSCs). MHY5456 significantly suppressed the expression of fibrosis-related genes and proteins. In vivo, administration of MHY5456 to mice fed a methionine-choline-deficient (MCD) diet alleviated hepatic fibrosis, inflammation, and lipid accumulation. These results show that FXR activation by MHY5456 modulates lipid metabolism and fibrotic pathways, suggesting its potential as a pharmacological candidate for liver and metabolic disorders, including MASLD. Further pharmacological and toxicological studies are needed to confirm its therapeutic relevance.
