Obesity can lead to hepatocellular carcinoma (HCC) development through the chronological induction of Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Steatohepatitis (NASH), Fibrosis and HCC. In the US, the incidences of NAFLD accounts for over 25% of the general population, approximately 85 million individuals. We generated a single cell transcriptomic atlas of liver cells during NAFLD-NASH-HCC progression. In support of this approach, we further provide detailed metabolic and functional of discrete cell types, generating a comprehensive map of the obesity-driven HCC in mice. Our study reveals the synergistic function of FABP5 in advancing HCC progression through 1) promoting cancer cell survival by shifting energy expenditure, preventing lipid peroxidation, and inducing Hippo pathway activation and 2) through suppressing macrophage T-cell cross-activation and anti-tumor immune response. Notably, we demonstrate the therapeutic potential of FABP5 through a dual-functional smallmolecule inhibitor that significantly ameliorates HCC progression. We found that our FABP5 specific inhibitor both reversed metabolic alterations that drive disease progression and induced anti-tumoral immune crosstalk, paving the foundation for future studies using this therapeutic modality.