High fat diet increases ISG15 expression by upregulating high mobility group A1 (HMGA1) in HCC cells, and upregulated ISG15 noncovalently binds with the GCLM subunit to enhance GCLM‐GCLC interaction, which subsequently increases glutathione production to reduce ROS and inhibit apoptosis of HCC cells. The gene discussed is ISG15; the disease is hepatocellular carcinoma.