Delineating exactly how TERT and β-catenin interplay would suggest promising treatment strategies for TERTp and CTNNB1-mutated HCC, including: (1) targeting non-canonical effects of TERT, critical for its tumor-promoting interactions with β-catenin; (2) targeting the interaction between TERT and β-catenin; and (3) combining relatively low doses of Wnt/β-catenin pathway and TERT inhibitors. This evidence concerns the gene CTNNB1 and hepatocellular carcinoma.