Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action

Abstract

Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.

Figure 1

Altered Wnt/β-catenin signaling in alcohol-related liver disease (ALD). A: Schematic diagram showing the activation of the Wnt/b-catenin pathway. B: Diagram illustrating the progression of ALD to hepatocellular carcinoma (HCC). β-Catenin activity is normally high in hepatocytes within Zone 3 due to pericentral Wnt stimulation. Wnt/β-catenin signaling is decreased during alcoholic steatosis (AS) and alcoholic steatohepatitis (ASH). This pathway is up-regulated in fibrotic and tumorigenic responses during alcoholic cirrhosis (AC) and HCC. IHC analysis for glutamine synthetase (GS) on human normal and HCC livers is shown in the middle panel. Dual staining for GS (red signal) and green fluorescent protein (GFP; green signal) labels high β-catenin activity in normal livers and HCC induced by streptozotocin and high-fat diet in the Streptozotocin and High-Fat Diet–Induced NASH Model (STAM) (bottom panel). C: Heatmaps show up-regulated (labeled in red) and down-regulated genes of Wnt/β-catenin signaling in the livers of patients with AH compared to those in normal donors. Data were based on publicly available GDS4389 data set (https://www.ncbi.nlm.nih.gov/gds) the diagrams were generated using BioRender.com (Toronto, ON, Canada). The arrow delineates the path of liver disease evolution, from normal tissue through ALD to liver cancer. Scale bars = 200 mm.