In this process, upregulated high mobility group A1 (HMGA1) enhances ISG15 transcription, upregulated ISG15 subsequently noncovalently binds with glutamate‐cysteine ligase modifier subunit (GCLM) and increases the GCLM‐glutamate‐cysteine ligase catalytic subunit (GCLC) interaction to form an ISG15/GCLM/GCLC complex, which has increased γ‐glutamate cysteine ligase (γ‐GCL) enzymatic activity that promotes glutathione synthesis to protect HCC cells from ROS‐induced apoptosis. Here, GCLM is linked to hepatocellular carcinoma.