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Repression of the ERRγ-CYP2E1 pathway by FGF4 mitigates alcohol-associated liver injury

Luyao Wang1,2, Wenliya Dong1, Lei Fan1,2

  • 1State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Hepatology (Baltimore, Md.)
|February 26, 2025
PubMed
Abstract

Insights

Fibroblast growth factor 4 (FGF4) is upregulated in alcohol-associated liver disease (ALD) and worsens liver injury by degrading ERRγ. Targeting FGF4 may offer new treatments for ALD.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • Alcohol-associated liver disease (ALD) is a major health concern with unclear injury mechanisms.
  • Fibroblast growth factor 4 (FGF4) is implicated in liver disease progression.

Purpose of the Study:

  • To investigate the role of FGF4 in the pathogenesis of alcohol-associated liver disease (ALD).

Main Methods:

  • Analysis of human liver specimens and mouse models of ALD.
  • Investigated the effects of hepatocyte-specific Fgf4 deletion and Fgfr4 knockout.
  • Utilized ERRγ inverse agonist GSK5182 and CYP2E1 inhibitor chlormethiazole (CMZ).

Main Results:

  • FGF4 mRNA and protein levels are elevated in ALD patients and mouse models, correlating with disease severity.
  • Hepatocyte-specific Fgf4 deletion exacerbated liver injury, increasing oxidative stress, inflammation, and apoptosis.
  • FGFR4-mediated phosphorylation and degradation of ERRγ by FGF4 was identified as a key mechanism.
  • Targeting FGFR4 or downstream pathways mitigated alcohol-induced liver injury.

Conclusions:

  • FGF4 acts as a stress-responsive regulator in liver pathophysiology via an FGFR4-ERRγ-CYP2E1 pathway.
  • FGF4 and its downstream signaling pathways represent potential therapeutic targets for ALD.
Keywords:
ERRγ-CYP2E1 axisFGF4FGFR4alcohol-associated liver diseaseliver damage

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