Nuclear translocation of GPS2 promotes activation of hepatic stellate cells by fatty acid oxidation pathway

  • Life Sci. 2026 Sep 15:401:124529. doi: 10.1016/j.lfs.2026.124529.
Haiqin Hong  1 ,  Li Wang  2 ,  Muran Lu  2 ,  Ziyi An  2 ,  Yanxia Shi  2 ,  Qi Deng  2 ,  Jingjing Wu  2 ,  Benwei Wang  2 ,  Jialu Lu  2 ,  Mengjun Li  2 ,  Yan Huang  3 ,  Weili Lu  4 ,  Fanrong Wu  5
Affiliations
  • 1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, China; Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
  • 2. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, China.
  • 3. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 4. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 5. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, China; Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei, 230601, China. Electronic address: [email protected].
PMID: 42276358 DOI: 10.1016/j.lfs.2026.124529
Abstract

Aims: To investigate the role of G protein pathway suppressor 2 (GPS2) nuclear translocation in hepatic stellate cell (HSC) activation and its underlying mechanisms in liver fibrosis.

Materials and methods: RNA Sequencing (RNA-seq) was performed to analyze differential gene expression among experimental groups. Fatty acid oxidation (FAO) was evaluated using FAO Blue staining. Co-immunoprecipitation (Co-IP) assays were conducted to investigate the interaction between GPS2 and its potential binding partners. In addition, HSC activation was induced by PDGF-BB, and cell proliferation, activation markers, and mitochondrial FAO levels were systematically assessed.

Key findings: GPS2 nuclear translocation was significantly increased during HSC activation. Inhibition of GPS2 nuclear translocation attenuated liver fibrosis and reduced HSC activation. Mechanistically, blocking GPS2 nuclear translocation weakened its interaction with PPARα. PPARα was found to regulate mitochondrial FAO, which in turn promoted HSC proliferation and activation. Suppression of PPARα reduced FAO and alleviated HSC activation.

Significance: This study identifies a novel mechanism whereby GPS2 nuclear translocation promotes HSC activation through interaction with PPARα and regulation of mitochondrial FAO. Targeting GPS2 nuclear translocation may represent a potential therapeutic strategy for liver fibrosis.

Keywords
Fatty acid oxidation, mitochondrion; G protein pathway suppressor 2; Liver fibrosis; Peroxisome proliferator-activated receptor alpha.
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