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Peer-reviewedCC BYInternational journal of molecular sciences

CWH43 Suppresses Ferroptosis-Associated Vulnerability Through Redox Adaptation in Colorectal Cancer

  • Kuei-Yen Tsai1,2,3
  • Po-Li Wei2,4,5,6,7
  • Cheng-Chin Lee1
  • Uyanga Batzorig8
  • Chien-Yu Huang9,10,11
  • Yu-Jia Chang1,5,11,12
12 affiliations
  1. 1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
  2. 2Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
  3. 3Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
  4. 4Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
  5. 5Center for Precision Medicine and Translational Cancer Research, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
  6. 6Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
  7. 7Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
  8. 8Department of Dermatology, Department of Cellular and Molecular Medicine, UCSD Stem Cell Program, University of California San Diego, La Jolla, CA 92093, USA
  9. 9School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan
  10. 10Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300044, Taiwan
  11. 11Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116079, Taiwan
  12. 12Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116079, Taiwan
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Abstract

Ferroptosis is an iron-dependent form of regulated cell death that has emerged as a potential vulnerability in cancer cells under therapeutic stress. However, the mechanisms by which colorectal cancer cells modulate ferroptosis susceptibility remain incompletely understood. In this study, we investigated the role of CWH43, a glycosylphosphatidylinositol-anchor biogenesis-related protein whose role in chemotherapy response has been unclear, in regulating redox balance and ferroptosis-associated vulnerability in colorectal cancer. Integrative analyses of clinical datasets, transcriptomic profiling, and functional experiments were performed using gain- and loss-of-function approaches in CRC cell models. We found that elevated CWH43 expression was associated with adverse clinical outcomes and reduced responsiveness to chemotherapy. Functionally, CWH43 attenuated ferroptosis-associated vulnerability by reducing intracellular reactive oxygen species and lipid peroxidation. Mechanistically, CWH43 promoted redox-adaptive programs involving activation of NRF2-dependent antioxidant signaling, upregulation of the cystine transporter SLC7A11, increased intracellular glutathione availability, and suppression of lipid peroxidation. Genetic or pharmacological disruption of SLC7A11 restored ferroptosis susceptibility and sensitized CWH43-overexpressing colorectal cancer cells to therapeutic stress, whereas ferrostatin-1 partially restored cell viability following erastin-containing treatments. Collectively, these findings identify CWH43 as a regulator of redox adaptation that modulates ferroptosis-associated vulnerability in colorectal cancer, providing insights into stress-adaptive survival mechanisms and chemotherapy resistance in cancer cells.

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Cite

BibTeXRIS
BibTeX
@article{tsai2026cwh43,
  title = {{CWH43 Suppresses Ferroptosis-Associated Vulnerability Through Redox Adaptation in Colorectal Cancer}},
  author = {Kuei-Yen Tsai and Po-Li Wei and Cheng-Chin Lee and Uyanga Batzorig and Chien-Yu Huang and Yu-Jia Chang},
  journal = {International journal of molecular sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27198830},
  url = {https://europepmc.org/article/PMC/PMC13665454},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CWH43 Suppresses Ferroptosis-Associated Vulnerability Through Redox Adaptation in Colorectal Cancer
AU  - Kuei-Yen Tsai
AU  - Po-Li Wei
AU  - Cheng-Chin Lee
AU  - Uyanga Batzorig
AU  - Chien-Yu Huang
AU  - Yu-Jia Chang
PY  - 2026
DA  - 2026/10/01
JO  - International journal of molecular sciences
DO  - 10.3390/ijms27198830
UR  - https://europepmc.org/article/PMC/PMC13665454
AB  - Ferroptosis is an iron-dependent form of regulated cell death that has emerged as a potential vulnerability in cancer cells under therapeutic stress. However, the mechanisms by which colorectal cancer cells modulate ferroptosis susceptibility remain incompletely understood. In this study, we investigated the role of CWH43, a glycosylphosphatidylinositol-anchor biogenesis-related protein whose role in chemotherapy response has been unclear, in regulating redox balance and ferroptosis-associated vulnerability in colorectal cancer. Integrative analyses of clinical datasets, transcriptomic profiling, and functional experiments were performed using gain- and loss-of-function approaches in CRC cell models. We found that elevated CWH43 expression was associated with adverse clinical outcomes and reduced responsiveness to chemotherapy. Functionally, CWH43 attenuated ferroptosis-associated vulnerability by reducing intracellular reactive oxygen species and lipid peroxidation. Mechanistically, CWH43 promoted redox-adaptive programs involving activation of NRF2-dependent antioxidant signaling, upregulation of the cystine transporter SLC7A11, increased intracellular glutathione availability, and suppression of lipid peroxidation. Genetic or pharmacological disruption of SLC7A11 restored ferroptosis susceptibility and sensitized CWH43-overexpressing colorectal cancer cells to therapeutic stress, whereas ferrostatin-1 partially restored cell viability following erastin-containing treatments. Collectively, these findings identify CWH43 as a regulator of redox adaptation that modulates ferroptosis-associated vulnerability in colorectal cancer, providing insights into stress-adaptive survival mechanisms and chemotherapy resistance in cancer cells.
SN  - 1422-0067
ER  -