Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer
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.
Authors
- Stephanie G. Craig (ORCID: https://orcid.org/0000-0002-5476-751X)
- Fiammetta Falcone
- Laura C. Greaves (ORCID: https://orcid.org/0000-0002-8071-5916)
- Aideen E. Ryan (ORCID: https://orcid.org/0000-0002-5831-6783)
- Bryan P. Marzullo (ORCID: https://orcid.org/0000-0002-1874-6906)
- Sudhir B. Malla (ORCID: https://orcid.org/0000-0001-5862-3815)
- Ciara Cunningham
- Sandra Van Schaeybroeck (ORCID: https://orcid.org/0000-0002-8853-1388)
- Brett Greer (ORCID: https://orcid.org/0000-0001-5039-0244)
- Daniel A. Tennant (ORCID: https://orcid.org/0000-0003-0499-2732)
- Andrew M. Shaw (ORCID: https://orcid.org/0000-0002-5611-3691)
- Rachel McCole
- Scott Monteith
- Niamh Doherty (ORCID: https://orcid.org/0000-0002-9638-5552)
- Brenton Cavanagh (ORCID: https://orcid.org/0000-0002-1582-5756)
- DB Longley
- Owen J. Sansom (ORCID: https://orcid.org/0000-0001-9540-3010)
- Brian Quinn (ORCID: https://orcid.org/0000-0002-4182-1118)
- Philip D. Dunne (ORCID: https://orcid.org/0000-0001-9160-283X)
- Sufyan Pandor
- William J. McDaid
- Connor Brown (ORCID: https://orcid.org/0009-0008-8914-1358)
- Peter F. Gallagher (ORCID: https://orcid.org/0000-0001-9712-0532)
- Arindam Banerjee (ORCID: https://orcid.org/0000-0002-1309-921X)
- Emma Kerr (ORCID: https://orcid.org/0000-0002-1952-4213)
- Nikita Lewis
- Emily Rogan
- Tríona Ní Chonghaile (ORCID: https://orcid.org/0000-0002-3041-4031)
- Callum Ormsby
- Letitia Mohammed-Smith
- Shaun Sharkey
- Matilda Downs
- Deborah Y. Moss
- Vicky Coyle
- Andrew Roe
- Aisling Y. Coughlan
- Ian G. Mills (ORCID: https://orcid.org/0000-0001-5347-5083)
- Melissa J. LaBonte
- Alexandra J. Emerson
- Rebecca Wurelly
- Christopher Elliott
- Omar Aftab (ORCID: https://orcid.org/0009-0009-6271-1493)
- Mary Mallon
- Sarah Gallagher
- Simon S. McDade
- Christopher McCann
- Aaron Philips
- Aoife Leonard
- Sarah Maguire
Institutions
- Thammasat University (TH)
- Queen's University Belfast (GB)
- Royal College of Surgeons in Ireland (IE)
- International Food Policy Research Institute (US)
- Ollscoil na Gaillimhe – University of Galway (IE)
- The Northern Ireland Cancer Centre (GB)
- Agilent Technologies (United Kingdom) (GB)
- Agri Food and Biosciences Institute (GB)
- University of Glasgow (GB)
- University of Birmingham (GB)
- Newcastle University (GB)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1038/s42255-026-01578-w
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Research UK
- Science Foundation Ireland
- Irish Research Council