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. The gene discussed is NFE2L2; the disease is neoplasm.