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

Chronic 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 (HCC). Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt HCC. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunological, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix (ECM) remodeling, and alters hepatocyte fate decisions, thereby creating a microenvironment that is highly conducive to carcinogenesis. Here, we provide a systemic 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 HCC. In addition, we explore emerging therapeutic strategies-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches-that offer potential for early identification and tailored therapy of ALD.