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Ligand-dependent reprogramming of HNF4A expression and function suppresses multistep hepatocarcinogenesis

Hikari Okada1,2, Kouki Nio1, Naoki Ohno3

  • 1Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Ishikawa, Japan.

Molecular Therapy. Oncology
|June 19, 2026
PubMed

Insights

Polyprenoic acid (PA) is the first identified ligand for hepatocyte nuclear factor 4 alpha (HNF4A), a liver tumor suppressor. PA prevents the progression of precancerous lesions to liver cancer (hepatocellular carcinoma).

Area of Science:

  • Hepatology
  • Oncology
  • Molecular Biology

Background:

  • Hepatocellular carcinoma (HCC) is a major global health concern.
  • Hepatocyte nuclear factor 4 alpha (HNF4A) acts as a tumor suppressor in the liver.
  • Effective agonists to activate HNF4A for cancer therapy remain elusive.

Purpose of the Study:

  • To identify novel ligands that bind and activate HNF4A.
  • To evaluate the therapeutic potential of identified ligands in preventing liver carcinogenesis.
  • To elucidate the mechanism of action of HNF4A activation in hepatocarcinogenesis.

Main Methods:

  • High-throughput screening to identify HNF4A ligands.
  • Reanalysis of clinical trial data for polyprenoic acid (PA).
  • In vivo studies using Pdgf-C transgenic mice and in vitro experiments with HNF4A knockdown/siRNA.

Main Results:

  • Polyprenoic acid (PA, peretinoin) was identified as the first direct HNF4A ligand.
  • PA suppressed the progression of dysplastic nodules to HCC in clinical data and mouse models.
  • PA selectively activated HNF4A P1, upregulating maturation markers and suppressing AFP, an effect dependent on HNF4A expression.

Conclusions:

  • HNF4A is a pharmacologically targetable tumor suppressor in the liver.
  • PA and similar compounds show promise for preventing liver cancer development.
  • Targeting HNF4A activation represents a novel strategy for chemoprevention of HCC.
Keywords:
chemopreventiondysplastic nodulehepatocellular carcinomahepatocyte nuclear factor 4 alphapolyprenoic acidtumor suppressor

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