{
  "abstract": "Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.",
  "abstract_shown": true,
  "affiliations": [
    "Johnston Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland, UK",
    "Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland",
    "Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland, Dublin, Ireland",
    "Agilent Technologies, Cheadle, UK",
    "Institute for Global Food Security, Queen's University Belfast, Belfast, Northern Ireland, UK",
    "Agri-Food and Biosciences Institute, Chemical Surveillance Branch, Veterinary Sciences Division, Belfast, Northern Ireland, UK",
    "International Joint Research Centre on Food Security (IJC-FOODSEC), Khong Luang, Thailand",
    "School of Food Science and Technology, Faculty of Science and Technology, Thammasat University, Khong Luang, Thailand",
    "Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland",
    "CRUK Scotland Institute, Glasgow, UK",
    "Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK",
    "School of Cancer Sciences, University of Glasgow, Glasgow, UK",
    "Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK",
    "Johnston Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland, UK. emma.kerr@qub.ac.uk"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 49,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Deborah Y. Moss"
    },
    {
      "affs": [
        0
      ],
      "name": "Connor N. Brown",
      "orcid": "0009-0008-8914-1358"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrew M. Shaw"
    },
    {
      "affs": [
        0
      ],
      "name": "Chris McCann"
    },
    {
      "affs": [
        0
      ],
      "name": "Nikita Lewis",
      "orcid": "0009-0006-6603-6251"
    },
    {
      "affs": [
        0
      ],
      "name": "Matilda Downs"
    },
    {
      "affs": [
        0
      ],
      "name": "Rebecca Wurelly"
    },
    {
      "affs": [
        0
      ],
      "name": "Ciara Cunningham"
    },
    {
      "affs": [
        0
      ],
      "name": "Aaron Philips"
    },
    {
      "affs": [
        0
      ],
      "name": "Niamh Doherty",
      "orcid": "0000-0002-9638-5552"
    },
    {
      "affs": [
        0
      ],
      "name": "Sarah Gallagher"
    },
    {
      "affs": [
        0
      ],
      "name": "William J. McDaid",
      "orcid": "0009-0007-3442-4820"
    },
    {
      "affs": [
        1
      ],
      "name": "Andrew J. Roe",
      "orcid": "0000-0002-6480-576X"
    },
    {
      "affs": [
        1
      ],
      "name": "Aisling Y. Coughlan",
      "orcid": "0000-0001-8614-7780"
    },
    {
      "affs": [
        2
      ],
      "name": "Brenton Cavanagh",
      "orcid": "0000-0002-1582-5756"
    },
    {
      "affs": [
        0
      ],
      "name": "Callum Ormsby"
    },
    {
      "affs": [
        0
      ],
      "name": "Fiammetta Falcone"
    },
    {
      "affs": [
        0
      ],
      "name": "Rachel McCole"
    },
    {
      "affs": [
        0
      ],
      "name": "Scott Monteith"
    },
    {
      "affs": [
        0
      ],
      "name": "Emily Rogan"
    },
    {
      "affs": [
        0
      ],
      "name": "Sudhir B. Malla",
      "orcid": "0000-0001-5862-3815"
    },
    {
      "affs": [
        0
      ],
      "name": "Alexandra J Emerson"
    },
    {
      "affs": [
        0
      ],
      "name": "Letitia Mohamed-Smith"
    },
    {
      "affs": [
        0
      ],
      "name": "Shaun Sharkey"
    },
    {
      "affs": [
        0
      ],
      "name": "Aoife Leonard"
    },
    {
      "affs": [
        0
      ],
      "name": "Peter F. Gallagher",
      "orcid": "0000-0001-9712-0532"
    },
    {
      "affs": [
        0
      ],
      "name": "Arindam Banerjee",
      "orcid": "0000-0002-1309-921X"
    },
    {
      "affs": [
        0
      ],
      "name": "Sandra Van Schaeybroeck",
      "orcid": "0000-0002-8853-1388"
    },
    {
      "affs": [
        3
      ],
      "name": "Sufyan Pandor"
    },
    {
      "affs": [
        4
      ],
      "name": "Brian Quinn",
      "orcid": "0000-0002-4182-1118"
    },
    {
      "affs": [
        5,
        4
      ],
      "name": "Brett Greer",
      "orcid": "0000-0001-5039-0244"
    },
    {
      "affs": [
        4,
        6,
        7
      ],
      "name": "Christopher Elliott"
    },
    {
      "affs": [
        0
      ],
      "name": "Sarah Maguire"
    },
    {
      "affs": [
        8
      ],
      "name": "Aideen E. Ryan",
      "orcid": "0000-0002-5831-6783"
    },
    {
      "affs": [
        9,
        0
      ],
      "name": "Philip D. Dunne",
      "orcid": "0000-0001-9160-283X"
    },
    {
      "affs": [
        0
      ],
      "name": "Mary G. Mallon"
    },
    {
      "affs": [
        0
      ],
      "name": "Stephanie G. Craig",
      "orcid": "0000-0002-5476-751X"
    },
    {
      "affs": [
        10
      ],
      "name": "Omar Aftab",
      "orcid": "0009-0009-6271-1493"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Laura C. Greaves",
      "orcid": "0000-0002-8071-5916"
    },
    {
      "affs": [
        12
      ],
      "name": "Bryan P. Marzullo",
      "orcid": "0000-0002-1874-6906"
    },
    {
      "affs": [
        12
      ],
      "name": "Daniel A. Tennant",
      "orcid": "0000-0003-0499-2732"
    },
    {
      "affs": [
        0
      ],
      "name": "Vicky M. Coyle",
      "orcid": "0000-0001-9566-4130"
    },
    {
      "affs": [
        0
      ],
      "name": "Ian Geoffrey Mills",
      "orcid": "0000-0001-5347-5083"
    },
    {
      "affs": [
        9,
        11
      ],
      "name": "Owen James Sansom",
      "orcid": "0000-0001-9540-3010"
    },
    {
      "affs": [
        1
      ],
      "name": "Tríona Ní Chonghaile",
      "orcid": "0000-0002-3041-4031"
    },
    {
      "affs": [
        0
      ],
      "name": "DB Longley"
    },
    {
      "affs": [
        0
      ],
      "name": "Simon S. McDade",
      "orcid": "0000-0002-3024-4773"
    },
    {
      "affs": [
        0
      ],
      "name": "Melissa J. LaBonte",
      "orcid": "0000-0002-0354-413X"
    },
    {
      "affs": [
        13
      ],
      "name": "Emma M. Kerr",
      "orcid": "0000-0002-1952-4213"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/41jny4ytc47dv.bib",
  "cited_by": 9,
  "doi": "10.1038/s42255-026-01578-w",
  "fulltext_url": null,
  "id": "41jny4ytc47dv",
  "issns": [
    "2522-5812"
  ],
  "landing_url": "https://doi.org/10.1038/s42255-026-01578-w",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1306|Cancer, Hypoxia, and Metabolism"
    ]
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  "openalex": "W7170162634",
  "pdf_url": "https://www.nature.com/articles/s42255-026-01578-w.pdf",
  "pmcid": "PMC13489958",
  "pmid": "42493590",
  "published": "2026-07-23",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/41jny4ytc47dv.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:07Z",
      "native_id": "W7170162634",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s42255-026-01578-w"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Hypoxia, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer",
  "title_text": "Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:43Z",
  "url": "https://research.draconitic.com/paper/41jny4ytc47dv",
  "venue": "Nature Metabolism",
  "versions": []
}