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FNDC4 regulates TGF-β1-induced hepatic stellate cell activation and liver fibrosis via the AMPK/YAP pathway

Gabriela Neira1, Cristina Montiel-Duarte2, Sara Becerril3

  • 1Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain; Institute for Nutrition and Health, University of Navarra, Pamplona, Spain.

Free Radical Biology & Medicine
|March 9, 2026
PubMed
Abstract

Insights

Fibronectin type III domain-containing 4 (FNDC4) protein reduces liver fibrosis by inhibiting hepatic stellate cell activation and fibrogenesis. Lower FNDC4 levels may worsen liver fibrosis in obesity-related metabolic dysfunction-associated steatotic liver disease (MASLD).

Area of Science:

  • Hepatology
  • Molecular Biology
  • Metabolic Disease Research

Background:

  • Fibronectin type III domain-containing 4 (FNDC4) protein influences insulin sensitivity, mitochondrial function, and inflammation.
  • Obesity-associated metabolic dysfunction-associated steatotic liver disease (MASLD) involves significant liver fibrosis.
  • The role of hepatocyte-derived FNDC4 in regulating liver fibrosis, particularly in MASLD, requires elucidation.

Purpose of the Study:

  • To investigate whether hepatocyte-derived FNDC4 limits transforming growth factor-β1 (TGF-β1)-induced hepatic stellate cell (HSC) activation and fibrogenesis.
  • To determine the contribution of FNDC4 to attenuating liver fibrosis in obesity-associated MASLD.
  • To explore the molecular mechanisms underlying FNDC4's effects on HSCs.

Main Methods:

  • Quantified plasma and hepatic FNDC4 expression and liver fibrosis in participants with severe obesity (n=200 plasma, n=75 hepatic).
  • Examined the effects of FNDC4 on human LX-2 HSC activation, fibrogenesis, and migration in vitro under TGF-β1 stimulation.
  • Utilized molecular techniques to investigate the role of AMPKα and YAP pathways.

Main Results:

  • FNDC4 expression inversely correlated with liver fibrosis severity; FNDC4 was hepatocyte-derived and localized near fibrotic regions.
  • FNDC4 treatment in HSCs promoted activation markers, increased mitochondrial activity, and glycolysis.
  • FNDC4 attenuated TGF-β1-induced collagen type I expression, apoptosis, and ROS production, while enhancing MMP-1 and GATA4.
  • FNDC4 inhibited TGF-β1-induced HSC migration by suppressing YAP activation via the AMPK pathway.

Conclusions:

  • Hepatocyte-derived FNDC4 acts as an anti-fibrogenic factor by modulating HSC activation and TGF-β1-driven fibrogenesis.
  • The AMPK/YAP pathway is crucial for FNDC4's anti-fibrotic effects on HSCs.
  • Reduced hepatic FNDC4 may contribute to persistent liver fibrosis in obesity-related MASLD.
Keywords:
FNDC4Hepatic stellate cell migrationLiver fibrosisMitochondrial dysfunctionObesity

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