A. Dependency on CCND1 gene correlates positively with sensitivity to CDK4 inhibitor palbociclib across a panel of human liver cancer cell lines. Dependency on CCND1 gene was determined by CRISPR gene editing from the Broad’s Project Achilles DepMap Public 19Q3 dataset. Palbociclib sensitivity was presented as IC50 from Sanger’s Genomics of Drug Sensitivity in Cancer dataset. B. CDK4 inhibitor palbociclib is effective in suppressing the progression of obese/diabetic liver tumors (n=5). Diagram depicts the protocol for orthotopic liver cancer and treatment model. Murine hepatoma was established in the liver of db/db mice via intrasplenic injection. Upon tumor established at day 10 post injection, daily treatment was given via oral gavage for six days, followed by tumor assessment. Tumor loads were measured by subtracting the weight of normal liver from the weights of tumor-bearing livers, or by quantifying the microscopic cancerous areas of the H&E slides. C. Liver cancers developed in obese/diabetic mice are more vulnerable to CDK4 inhibitor (n=5). Upon hepatoma development in lean or obese/diabetic mice, treatments with either vehicle (Veh) or palbociclib were given at a relatively lower dose, followed by tumor assessment.