This study, through an integrated analysis of single-cell, spatial, and bulk transcriptomic data, has successfully identified a core network of nine tumor-specific transcription factors (TFs)—HTATIP2, HES6, ILF2, E2F1, MYBL2, DDIT3, FOXM1, HMGA1, and ETV4—that orchestrates the malignant programs of hepatocellular carcinoma (HCC). Here, HES6 is linked to hepatocellular carcinoma.