Alcohol Dehydrogenase 4‐Mediated Retinol Metabolism Inhibits Hepatocellular Carcinoma Progression Through Inhibiting the Wnt/β‐Catenin Pathway

ABSTRACT Hepatocellular carcinoma (HCC) ranks third in global cancer‐related mortality, with limited therapies for advanced stages. Retinol, the alcohol form of vitamin A, has long been associated with liver diseases. Plasma retinol levels have been inversely correlated with the risk and poor prognosis of HCC. In this study, transcriptome data analysis identified retinol metabolism as the seventh KEGG‐dysregulated pathway in cirrhosis tissue, ascending to the top position in HCC tissue compared to normal tissue. Specifically, a consistent downregulation of ADH4 (alcohol dehydrogenase 4), the retinol dehydrogenase among human ADHs, was observed, which correlated with poor prognosis in HCC patients. In vivo experiments demonstrated that silencing ADH4 enhances liver fibrosis and the progression of HCC. Mechanistically, ADH4 elevated intracellular levels of RA (retinoic acid), a biologically active derivative of retinol. RA‐activated retinoid receptors RARs/RXRs, leading to inhibition of the downstream Wnt/β‐catenin pathway and thereby hindering HCC progression. In contrast, the knockdown of ADH4 in hepatocytes triggers apoptosis. Notably, additional results demonstrated that the combined treatment of RA and cisplatin achieved synergistic antitumor effects in a mouse HCC model. In summary, our research elucidates that ADH4‐mediated RA production suppresses HCC growth, providing a theoretical foundation for HCC treatment.