Since ROS are usually upregulated in tumor cells, they rely heavily on the antioxidant system to effectively keep ROS below lethal levels and are more vulnerable to any insults that disrupt ROS homeostasis.[23, 24] Here, we report a novel role of DDRGK1 in regulating key ROS proteins by competing with NRF2 to bind to Kelch‐like ECH‐associated protein 1 (KEAP1), blocking the initiation of ubiquitin‐proteasome‐mediated degradation by CUL3 (an E3 ligase of NRF2), thus broadly regulating the antioxidant system. The gene discussed is DDRGK1; the disease is neoplasm.