Hepatoblastoma (HB) is the predominant primary malignant liver tumor in childhood. Concomitant YAP and β-Catenin activation occurs in most HB. However, the signaling pathways distinctively regulated by YAP and β-Catenin protooncogenes in HB remain unexplored.We engineered an inducible HB murine model using hydrodynamic injection to deliver transposon plasmids encoding constitutive YAP and doxycycline (Dox)-inducible ΔN90-β-Catenin(YAP/TRE-β-Catenin). Gene expression patterns in mouse HB lesions upon short-term Dox withdrawal, i.e., tumors still existed, but ΔN90-β-Catenin was turned OFF, were analyzed. Mice rapidly developed aggressive HB lesions when fed doxycycline. However, upon Dox withdrawal, HB regressed, although tumors did not completely disappear over a long time. At the molecular level, YAP and β-Catenin were found to regulate distinct gene expression programs in HB. Specifically, YAP controls the Hippo and metabolism-related pathways, whereas β-Catenin modulates immune-related pathways contributing to immune exclusion in the tumor microenvironment. Furthermore, we identified the transcription factor ONECUT1 as a tumor suppressor gene downregulated by activated β-Catenin in HB. Low ONECUT1 expression also characterizes human HB, and co-expression of ONECUT1 strongly suppressed YAP/β-Catenin-driven HB formation in mice. Mechanistically, ONECUT1 functions downstream of activated β-Catenin and negatively regulates tumor cell glycolysis.We show that suppressing activated β-Catenin could hamper HB progression in vivo by affecting pathways distinct from those regulated by YAP in HB. Inhibition of ONECUT1 expression by β-Catenin might represent a critical molecular event leading to HB formation.Copyright © 2025 American Association for the Study of Liver Diseases.