Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Novel Anti-Fibrotic Role of G-Protein-Coupled Receptor 119 in Hepatic Stellate Cells

  • Jeongwoo Park (College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University) ;
  • Min Hoo Lee (College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University) ;
  • Hyun Young Kim (College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University) ;
  • Hyo Seon Kim (College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University) ;
  • Sang Kyum Kim (College of Pharmacy, Chungnam National University) ;
  • Jin Won Yang (College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University) ;
  • Keon Wook Kang (College of Pharmacy, Research Institute of Pharmaceutical Sciences and Natural Product Research Institute, Seoul National University)
  • Received : 2026.03.13
  • Accepted : 2026.03.26
  • Published : 2026.05.01
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Abstract

Liver fibrosis arises from chronic hepatic injury and remains a major clinical challenge due to the lack of effective therapies. Although G-protein-coupled receptor 119 (GPR119) has been explored as a metabolic target in type 2 diabetes, its role in liver fibrogenesis is not well understood. In this study, the protein and mRNA expression of GPR119 were detected in mouse primary hepatic stellate cells (HSCs) using immunostaining and reverse transcriptase-polymerase chain reaction. The anti-fibrotic activities of GPR119 agonists were assessed in primary HSCs, LX-2 cells, and a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. Treatment with the GPR119 agonists MBX-2982 and GSK1292263 inhibited HSC activation, suppressed transforming growth factor-β1 (TGFβ1)-induced Smad2/3 phosphorylation, and reduced the expression of fibrogenic genes. In vivo, oral administration of MBX-2982 attenuated collagen accumulation and decreased hepatic α-smooth muscle actin and TGFβ expression in CCl4-treated mice. Mechanistically, MBX-2982 activated AMP-activated protein kinase (AMPK), and pharmacological inhibition of AMPK reversed its anti-fibrogenic effects. MBX-2982 further reduced Smad3 acetylation by disrupting the interaction between Smad3 and p300 and promoting AMPK-dependent proteasomal degradation of p300. These results identify GPR119 as a regulator of HSC activation and highlight GPR119 agonists as promising therapeutic candidates for liver fibrosis.

Keywords

Acknowledgement

This work was supported by the Bio&Medical Technology Development Program of the NRF funded by the Korea government (MSIP) (RS-2022-NR067269) and the Ministry of Education (RS-2025-25397599).

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