NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer
7 affiliations
- 1Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.
- 2Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
- 3Universitat de Barcelona, 08028 Barcelona, Spain.
- 4Leicester Cancer Research Centre, University of Leicester, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 7LX, UK.
- 5Institute for Structural and Chemical Biology and School of Chemistry, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK.
- 6Department of Biomedical Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Catalunya 08195, Spain.
- 7Leicester van Geest Multi-Omics Facility, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 7RH, UK.
Abstract
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.
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BibTeX
@article{morellato2026nrf2,
title = {{NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer}},
author = {Agustín E. Morellato and Natividad Alquezar-Artieda and Alejandro Guerrero-Maldonado and Rajinder Singh and Lilla Beja and Carla Umansky and Laura Perich-Pallaruelo and Mireia Pellicer and Paula Fernandez-Deu and Nicolas Aira and Nour Bourached-Silva and Uciel Chorostecki and Donald J. L. Jones and Gaël Roué and Richard J. Hopkinson and Lucas B. Pontel},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aea1431},
url = {https://www.science.org/doi/10.1126/sciadv.aea1431},
note = {CC BY},
}
RIS
TY - JOUR
TI - NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer
AU - Agustín E. Morellato
AU - Natividad Alquezar-Artieda
AU - Alejandro Guerrero-Maldonado
AU - Rajinder Singh
AU - Lilla Beja
AU - Carla Umansky
AU - Laura Perich-Pallaruelo
AU - Mireia Pellicer
AU - Paula Fernandez-Deu
AU - Nicolas Aira
AU - Nour Bourached-Silva
AU - Uciel Chorostecki
AU - Donald J. L. Jones
AU - Gaël Roué
AU - Richard J. Hopkinson
AU - Lucas B. Pontel
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aea1431
UR - https://www.science.org/doi/10.1126/sciadv.aea1431
AB - 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.
SN - 2375-2548
ER -