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

Activation of tumor suppressors represents an attractive strategy for cancer treatment. Hepatocyte nuclear factor 4 alpha (HNF4A) functions as a tumor suppressor in the liver by inhibiting hepatocyte proliferation; however, no effective agonists have been identified. Here, we aimed to identify novel ligands for HNF4A and evaluate their role in hepatocarcinogenesis. We identified polyprenoic acid (PA, peretinoin) as the first ligand capable of directly binding HNF4A. Reanalysis of prior clinical trial data revealed that PA suppressed the progression of dysplastic nodules (DNs) to hepatocellular carcinoma (HCC), while showing no effect on local HCC recurrence after initial treatment. Consistently, PA inhibited DN growth but not established HCC in Pdgf-C transgenic mice. Mechanistically, PA selectively bound to the HNF4A P1 isoform, enhancing its transcriptional activity and upregulating hepatocyte maturation markers (ALB, TTR, and SLCO1B3), while suppressing alpha-fetoprotein expression driven by the HNF4A P2 isoform. Importantly, hepatocyte-specific Hnf4a knockdown or lipid-nanoparticle-mediated Hnf4a siRNA abrogated the protective effects of PA. These findings establish HNF4A as a pharmacologically controllable tumor suppressor and highlight PA-like compounds as promising agents for preventing liver carcinogenesis.