In DEN‐induced HCC models (Figure 6A), while HFD feeding significantly increased the total volume and number of large HCC tumors (diameters ≥ 5 mm) in WT mice, HCC progression was significantly inhibited in HFD‐fed Isg15‐KO mice (Figure 6B,C, Supporting Information). Here, ISG15 is linked to hepatocellular carcinoma.