• Tumor cells tend to be more iron-dependent when they are rapidly proliferating. In this case, tumor cells more sensitive to ferroptosis due to higher levels of intracellular iron and ROS.• NRF2 has a dual role in tumor progression: lack of NRF2 activity can lead to early tumorigenesis, whereas high basal NRF2 activity can trigger tumor progression and resistance to therapy. The gene discussed is NFE2L2; the disease is neoplasm.