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. The gene discussed is EPCAM; the disease is hepatocellular carcinoma.