In the present work, we show for the first time that the non-tumorigenic variant of FGF19, namely FGF19-M52, retaining its intrinsic metabolic effects on Cyp7a1 repression and consequent reduction of hepatic BA synthesis, protects Abcb4−/− and Fxr−/− mice against spontaneous hepatocarcinogenesis thus electing hepatic BA suppression as a metabolic strategy to prevent fibrosis and HCC in susceptible models. The gene discussed is ABCB4; the disease is hepatocellular carcinoma.