Together, in contrast to Alb-Cre strain-driven developmental Sox9 removal, tumor-specific acute Sox9 elimination robustly prevents Akt-YAP1- or Akt-NRAS-mediated cHCC/CCA formation, irrespective of the lineage of liver cancer, while Dnmt1 is partially responsible for Sox9 contribution in Akt-NRAS liver cancer development. Here, SOX9 is linked to neoplasm.