Together, under high‐fat stress, upregulated ISG15 non‐covalently binds GCLM to form a ISG15/GCLM/GCLC complex with enhanced γ‐GCL activity, thus increasing glutathione production and playing an oncogenic role in HCC cells by reducing ROS‐induced apoptosis (Figure 6M), which may be further explored to develop γ‐GCL inhibitors for the treatment of liver and lung cancers by promoting apoptosis. This evidence concerns the gene GCLC and hepatocellular carcinoma.