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Lookup NU author(s): Omar Aftab, Professor Laura GreavesORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026. 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.
Author(s): Moss DY, Brown CN, Shaw AM, McCann C, Lewis N, Downs M, Wurelly R, Cunningham C, Philips A, Doherty N, Gallagher S, McDaid WJ, Roe A, Coughlan AY, Cavanagh B, Ormsby C, Falcone F, McCole R, Monteith S, Rogan E, Malla SB, Emerson AJ, Mohammed-Smith L, Sharkey S, Leonard A, Gallagher PF, Banerjee A, Van Schaeybroeck S, Pandor S, Quinn B, Greer B, Elliott C, Maguire S, Ryan AE, Dunne PD, Mallon M, Craig S, Aftab O, Greaves LC, Marzullo BP, Tennant DA, Coyle V, Mills IG, Sansom O, Ni Chonghaile T, Longley DB, McDade SS, LaBonte MJ, Kerr EM
Publication type: Article
Publication status: Published
Journal: Nature Metabolism
Year: 2026
Pages: Epub ahead of print
Online publication date: 23/07/2026
Acceptance date: 24/06/2026
Date deposited: 04/08/2026
ISSN (electronic): 2522-5812
Publisher: Springer Nature
URL: https://doi.org/10.1038/s42255-026-01578-w
DOI: 10.1038/s42255-026-01578-w
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