In this study, we further provided evidence that (1) the content of unsaturated fatty acids was increased in MYCNhigh EpCAM+ CSC-like HCC cells; (2) inhibition of lipid desaturation using either the chemical inhibitor or siRNA/shRNA against SCD1 suppressed cell proliferation as well as MYCN gene expression in the MYCNhigh HCC cells grown as both monolayer and spheres. This evidence concerns the gene SCD and hepatocellular carcinoma.