Here, we revealed that liver-specific developmental Sox9 elimination using Alb-Cre;Sox9(flox/flox) (LKO) and CRISPR/Cas9-based tumor-specific acute Sox9 elimination (CKO) in SB-HDTVI-based Akt-YAP1 (AY) and Akt-NRAS (AN) cHCC-CCA models showed contrasting responses. The gene discussed is SOX9; the disease is cholangiocarcinoma.