Progression of chronic liver injury to fibrosis, abnormal liver regeneration and hepatocellular carcinoma (HCC) are driven by a dysregulated dialog between epithelial cells with their micro-environment, in particular immune, fibroblasts and endothelial cells. There is currently no antifibrogenic therapy and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and non-parenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we will discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration and HCC.