The article provides a comprehensive analysis of the Wnt/β-Catenin signaling pathway in hepatocellular carcinoma (HCC), highlighting its pathogenic role and therapeutic potential. HCC is the most common primary malignant liver tumor, with a high mortality rate due to its late-stage diagnosis and poor prognosis. The Wnt/β-Catenin signaling pathway, a highly conserved pathway involved in various biological processes, is often abnormally activated in HCC, contributing to tumor initiation, progression, and therapy resistance. The article discusses the physiological functions of the Wnt/β-Catenin pathway in liver development, metabolic zonation, and regeneration. It also explores the mechanisms by which this pathway is activated in HCC, including mutations in CTNNB1, loss of function or mutation of Axin, GSK-3β, and APC, and the upregulation of Wnt ligands and their receptors. The article further examines the role of the Wnt/β-Catenin pathway in HCC progression, including cancer stem cell maintenance, proliferation, invasion, and metastasis, as well as its involvement in epithelial-mesenchymal transition, glycolysis, angiogenesis, and hypoxia. Additionally, the article reviews the pathway's role in therapy resistance, such as multidrug resistance and resistance to chemotherapy, radiation therapy, and immunotherapy. Finally, the article discusses potential therapeutic strategies targeting the Wnt/β-Catenin pathway, including pharmaceuticals, natural bioactive compounds, and genetic tools, while acknowledging the challenges and limitations of current approaches.The article provides a comprehensive analysis of the Wnt/β-Catenin signaling pathway in hepatocellular carcinoma (HCC), highlighting its pathogenic role and therapeutic potential. HCC is the most common primary malignant liver tumor, with a high mortality rate due to its late-stage diagnosis and poor prognosis. The Wnt/β-Catenin signaling pathway, a highly conserved pathway involved in various biological processes, is often abnormally activated in HCC, contributing to tumor initiation, progression, and therapy resistance. The article discusses the physiological functions of the Wnt/β-Catenin pathway in liver development, metabolic zonation, and regeneration. It also explores the mechanisms by which this pathway is activated in HCC, including mutations in CTNNB1, loss of function or mutation of Axin, GSK-3β, and APC, and the upregulation of Wnt ligands and their receptors. The article further examines the role of the Wnt/β-Catenin pathway in HCC progression, including cancer stem cell maintenance, proliferation, invasion, and metastasis, as well as its involvement in epithelial-mesenchymal transition, glycolysis, angiogenesis, and hypoxia. Additionally, the article reviews the pathway's role in therapy resistance, such as multidrug resistance and resistance to chemotherapy, radiation therapy, and immunotherapy. Finally, the article discusses potential therapeutic strategies targeting the Wnt/β-Catenin pathway, including pharmaceuticals, natural bioactive compounds, and genetic tools, while acknowledging the challenges and limitations of current approaches.