NRF2-mediated ferroptosis suppression defines a cancer-specific vulnerability in tumors

NRF2 is a master regulator of redox and metabolic homeostasis that protects normal tissues from stress but is frequently hijacked by cancers to sustain survival and therapy resistance. Although NRF2 is dispensable for normal tissue function, its role in maintaining cancer cells within the native tumor microenvironment has remained undefined. Here, we uncover an essential and previously unrecognized tumor-specific dependency on NRF2. Using an inducible Kras^FSF.G12D/+;Nrf2^Fl/Fl;Rosa26^{CreERT2/CreERT2} (KNR) mouse lung cancer model, we demonstrate that NRF2 deletion alone, without pharmacologic intervention, eradicates cancer cells, reduces tumor burden, and prolongs survival. Single-cell RNA sequencing coupled with artificial intelligence-based genotype classification revealed that NRF2-deleted cancer cells are selectively eliminated, whereas non-cancerous cells tolerate NRF2 loss. Mechanistically, NRF2 deletion induces ferroptosis, a regulated iron-dependent cell death pathway, evidenced by induction of canonical ferroptotic genes (Ptgs2, Acsl4, Tfrc) and protein markers (SO₂/₃-PRDX3, COX2, TfR1). Importantly, these data support that NRF2 loss induces ferroptotic cell death in vivo within established tumors, in the absence of exogenous ferroptosis inducers or external stress. These findings establish that cancer cells depend on NRF2 to suppress intrinsic ferroptotic stress for survival, a dependency not shared by normal tissues. This discovery fundamentally redefines the pathological role of NRF2 and positions NRF2 inhibition as a standalone, tumor-selective therapeutic strategy to eliminate Kras-driven malignancies by unleashing ferroptosis.