β-Catenin Signaling in Hepatocellular Carcinoma: Mechanisms of Therapeutic Resistance and Emerging Therapeutic Strategies

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with poor patient outcomes largely attributable to late diagnosis and the frequent development of therapeutic resistance. Although advances in chemotherapy, targeted therapies, immunotherapy, and combination regimens have improved treatment options, durable clinical responses remain limited. This review synthesizes current evidence on the role of β-catenin signaling in HCC progression and therapeutic resistance, emphasizing the molecular mechanisms underlying aberrant pathway activation and its interactions with other oncogenic signaling networks. The review examines how constitutive β-catenin activation promotes tumor growth, cancer stem cell maintenance, metabolic reprogramming, immune evasion, and resistance to chemotherapy, targeted therapies, and immune checkpoint inhibitors. In addition, emerging therapeutic strategies targeting β-catenin are discussed, including inhibition of β-catenin transcriptional activity, modulation of upstream Wnt signaling, direct suppression of CTNNB1 expression using nucleic acid-based approaches, and interventions targeting the immune and metabolic consequences of pathway activation. Collectively, the evidence identifies β-catenin as a central mediator of HCC progression and treatment resistance while highlighting its potential as a therapeutic target. A deeper understanding of β-catenin-driven mechanisms may facilitate the development of more effective therapeutic strategies and improve clinical outcomes for patients with HCC.