In this study, we unveil the previously uncharacterized tumor-promoting function and clinical significance of the CDK4/6-DUB3 axis in stabilizing YAP1, providing preclinical evidence that targeting CDK4/6 and DUB3 constitutes an effective strategy for suppressing tumor growth and overcoming chemo-resistance in HCC (Fig. 6M). This evidence concerns the gene YAP1 and hepatocellular carcinoma.