{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.",
    "Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.",
    "Universitat de Barcelona, 08028 Barcelona, Spain.",
    "Leicester Cancer Research Centre, University of Leicester, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 7LX, UK.",
    "Institute for Structural and Chemical Biology and School of Chemistry, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK.",
    "Department of Biomedical Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Catalunya 08195, Spain.",
    "Leicester van Geest Multi-Omics Facility, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 7RH, UK."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Agustín E. Morellato",
      "orcid": "0000-0003-2750-720X"
    },
    {
      "affs": [
        0
      ],
      "name": "Natividad Alquezar-Artieda",
      "orcid": "0009-0004-5313-4376"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Alejandro Guerrero-Maldonado",
      "orcid": "0009-0008-9546-1649"
    },
    {
      "affs": [
        3
      ],
      "name": "Rajinder Singh",
      "orcid": "0000-0002-1999-4119"
    },
    {
      "affs": [
        4
      ],
      "name": "Lilla Beja"
    },
    {
      "affs": [
        1
      ],
      "name": "Carla Umansky",
      "orcid": "0000-0002-9364-3544"
    },
    {
      "affs": [
        0
      ],
      "name": "Laura Perich-Pallaruelo",
      "orcid": "0009-0005-1806-6459"
    },
    {
      "affs": [
        0
      ],
      "name": "Mireia Pellicer",
      "orcid": "0009-0007-2801-7671"
    },
    {
      "affs": [
        0
      ],
      "name": "Paula Fernandez-Deu"
    },
    {
      "affs": [
        5
      ],
      "name": "Nicolas Aira"
    },
    {
      "affs": [
        0
      ],
      "name": "Nour Bourached-Silva",
      "orcid": "0009-0009-2195-4667"
    },
    {
      "affs": [
        5
      ],
      "name": "Uciel Chorostecki",
      "orcid": "0000-0003-2229-6853"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Donald J. L. Jones",
      "orcid": "0000-0001-6583-870X"
    },
    {
      "affs": [
        0
      ],
      "name": "Gaël Roué",
      "orcid": "0000-0003-0245-2257"
    },
    {
      "affs": [
        4
      ],
      "name": "Richard J. Hopkinson",
      "orcid": "0000-0001-7610-8163"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Lucas B. Pontel",
      "orcid": "0000-0001-8384-3422"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ed6r46t96kw5m.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aea1431",
  "fulltext_url": "https://europepmc.org/articles/PMC13693651",
  "id": "ed6r46t96kw5m",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aea1431",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Ferroptosis and cancer prognosis"
    ]
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  "openalex": "W7213419615",
  "pdf_url": "https://europepmc.org/articles/PMC13693651?pdf=render",
  "pmcid": "PMC13693651",
  "pmid": "42913006",
  "published": "2026-10-23",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/ed6r46t96kw5m.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aea1431",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aea1431"
    },
    {
      "first_seen": "2026-10-30T12:20:03Z",
      "native_id": "MED:42913006",
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      "url": "https://europepmc.org/article/MED/42913006"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Ferroptosis and cancer prognosis",
      "subfield": "general"
    }
  ],
  "title": "NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer",
  "title_text": "NRF2 coordinates cystine import and glutathione use to sustain ferroptosis resistance and formaldehyde tolerance in cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:03Z",
  "url": "https://research.draconitic.com/paper/ed6r46t96kw5m",
  "venue": "Science Advances",
  "versions": []
}