NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer.

Cancer cells must balance detoxification of reactive metabolic by-products while preserving redox homeostasis, but how this trade-off is managed remains unclear. The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor-erythroid 2-related factor 2 (NRF2) pathway, a key regulator of antioxidant defenses, is frequently hyperactivated in cancer. Formaldehyde, a genotoxic one-carbon by-product, is typically detoxified via glutathione (GSH), which is also essential for suppressing ferroptotic cell death. Here, we show that NRF2 promotes formaldehyde tolerance through up-regulation of the cystine transporter SLC7A11, enabling a protective mechanism that is largely independent of GSH, which remains necessary for ferroptosis resistance. In NRF2-active cells, formaldehyde reacts with cysteine to form a thiazolidine conjugate, and the combination of formaldehyde stress and SLC7A11 inhibition activates the integrated stress response, suppresses global protein synthesis, and markedly compromises cell viability. Together, these findings reveal that NRF2 coordinates ferroptosis resistance and formaldehyde tolerance, exposing a cancer vulnerability through combined inhibition of cystine uptake and GSH synthesis.