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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
Summary
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.
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