A research team from the Air Force Medical University in China has uncovered a critical mechanistic link between retinol metabolism and the progression of hepatocellular carcinoma (HCC).

Published in Medcomm-Oncology, their study identifies alcohol dehydrogenase 4 (ADH4), the enzyme responsible for converting retinol (vitamin A) to its bioactive metabolite retinoic acid (RA), serves as a key suppressor of HCC.

While retinol metabolism has long been associated with liver physiology, its specific role in oncogenic regulation has remained poorly understood.

By conducting analysis‌ of HCC transcriptomic profiling, the researchers identified retinol metabolism as the most significantly dysregulated pathway in HCC tissues.

They observed a marked downregulation of ADH4 expression in tumour tissues compared to adjacent cirrhotic regions, and low ADH4 levels were linked to poorer patient survival and higher recurrence rates, underscoring its potential as a prognostic biomarker.

Functional studies revealed that silencing ADH4 in HCC cell lines heightened proliferative activity and colony formation, while forced ADH4 expression in cells with low endogenous levels reversed these oncogenic traits.

Mechanistic investigations further demonstrated that loss of ADH4 reduces intracellular RA concentrations, thereby impairing the activation of retinoid receptors (RAR/RXR).

These nuclear receptors are known to counteract the Wnt/β-catenin signalling pathway, a frequently hyperactivated oncogenic cascade in HCC that drives unchecked cellular proliferation.

Through this regulatory mechanism, ADH4-mediated RA production emerges as a critical metabolic checkpoint in hepatocarcinogenesis.

In vivo experiments showed that ADH4 overexpression significantly reduced tumour burden.

Moreover, the combination of RA with cisplatin demonstrated synergistic anti-tumour efficacy, leading to greater reductions in tumour growth compared to either treatment alone.

This combinatorial approach also improved survival rates without inducing significant systemic toxicity, addressing a major challenge associated with current HCC therapies.

Interestingly, the study also uncovered a dual role for ADH4: while its deficiency promotes HCC progression, its overexpression promotes liver fibrosis by inducing apoptosis in normal hepatocytes.

This tissue-specific dichotomy highlights the complex interplay of retinol metabolism in hepatic homeostasis and cancer progression, emphasising the need for therapeutic strategies that selectively target malignant cells while preserving normal liver function.

These findings suggest two promising translational applications: the use of ADH4 expression levels for prognostic stratification of HCC patients and the implementation of RA-based combination therapies to improve treatment outcomes.

Future research should aim to validate these results in larger clinical cohorts and explore the immunomodulatory effects of RA within the tumour microenvironment to further refine therapeutic interventions.

Source: Sichuan International Medical Exchange and Promotion Association