In summary, our data implicate that NAC and GSH as exogenous antioxidants promote HCC formation, enhance tumor growth, and counteract the therapeutic effect of Sorafenib both in vitro and in vivo by reducing the intracellular ROS levels and desensitizing NRF2/GCLC-related antioxidant production pathways. Here, NFE2L2 is linked to hepatocellular carcinoma.