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WNT–β-catenin signalling in hepatocellular carcinoma: from bench to clinical trials

Nature Reviews Gastroenterology & Hepatology (2025)Cite this article

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Abstract

WNT–β-catenin activation is observed in around 50% of all patients with hepatocellular carcinoma (HCC), through either gain-of-function mutations in CTNNB1 (which encodes β-catenin) or loss-of-function mutations in AXIN1 or APC. Currently, first-line therapies for HCC are immune checkpoint inhibitor (ICI) combinations, and β-catenin-active HCCs have garnered increased attention due to their unique tumour immune microenvironment (TIME). This pathway is known to drive an immune-excluded TIME, but clinical investigations have provided a more nuanced perspective, with the emergence of a new ‘immune-like’ subclass of HCC that is paradoxically enriched for CTNNB1 mutations and has high levels of T cell infiltration. As such, patients and animal models with β-catenin activation treated with ICIs exhibit heterogeneous responses. Additionally, these tumours exhibit higher fatty acid oxidation to fuel tumour growth owing to a unique metabolic milieu shaped by zone 3 metabolism, which is a physiological function of WNT–β-catenin signalling in the liver lobule. Biomarkers to detect molecular subclasses of patients for targeted therapies are being developed. In this Review, we discuss advances in our understanding of the TIME and metabolism of β-catenin-active HCC, driven by in vitro and in vivo models and single-cell and spatial sequencing, and their implications for the treatment of a subset of HCCs using precision therapies against WNT–β-catenin signalling.

Key points

  • The WNT–β-catenin pathway regulates metabolic zonation in the liver lobule and regulates expression of genes in hepatocytes residing in zone 3.

  • Activation of the WNT–β-catenin pathway is evident in a notable subset of hepatocellular carcinomas (HCC) due to multiple mechanisms including missense mutations in CTNNB1.

  • HCCs driven by mutations in CTNNB1 exhibit unique zone 3 metabolic phenotypes and tumour cell metabolism.

  • β-Catenin-active HCCs have a unique tumour immune microenvironment due to both tumour cell-intrinsic and tumour cell-extrinsic mechanisms.

  • Preclinical models and multi-omics clinical studies have been key to understanding the unique biology of the molecular subset of HCCs with WNT–β-catenin activation.

  • Current precision medicine-based clinical trials are exploiting novel metabolic vulnerabilities or directly targeting the WNT–β-catenin pathway for HCC treatment.

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Fig. 1: Multiple roles of β-catenin in hepatocellular carcinoma.
Fig. 2: Theranostic work-up to assess CTNNB1-mutated HCC for precision therapy.
Fig. 3: Single-cell and spatial transcriptomic workflows to study CTNNB1-mutated HCC.
Fig. 4: Therapies for CTNNB1-mutated HCC for precision therapy.

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Acknowledgements

S.P.M. was supported by NIH grants R01CA251155, R01CA250227, 5R01DK062277 and Senior Vice Chancellor Endowed Chair in Pathobiology and Therapeutics. B.M.L. was supported in part by T32EB001026 and F30CA284540.

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Authors and Affiliations

  1. Organ Pathobiology and Therapeutics Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Brandon M. Lehrich & Satdarshan P. Monga

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Brandon M. Lehrich & Satdarshan P. Monga

  3. Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Brandon M. Lehrich & Satdarshan P. Monga

  4. Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA

    Brandon M. Lehrich

  5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Satdarshan P. Monga

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Correspondence to Satdarshan P. Monga.

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S.P.M. received funding and/or materials from Alnylam Pharmaceuticals, Dicerna, Fog and Revolution Medicines; was a consultant for ALIGOS; and is currently a consultant or scientific adviser to Alnylam Pharmaceuticals, UbiquiTx and Vicero Bio. B.M.L. declares no competing interests.

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Lehrich, B.M., Monga, S.P. WNT–β-catenin signalling in hepatocellular carcinoma: from bench to clinical trials. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01127-y

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