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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms27198830","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:50:38Z","timestamp":1790959838000},"page":"8830","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CWH43 Suppresses Ferroptosis-Associated Vulnerability Through Redox Adaptation in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8592-6336","authenticated-orcid":false,"given":"Kuei-Yen","family":"Tsai","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7275-2661","authenticated-orcid":false,"given":"Po-Li","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Center for Precision Medicine and Translational Cancer Research, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Chin","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8565-4713","authenticated-orcid":false,"given":"Uyanga","family":"Batzorig","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Department of Cellular and Molecular Medicine, UCSD Stem Cell Program, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan"},{"name":"Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300044, Taiwan"},{"name":"Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116079, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3978-3244","authenticated-orcid":false,"given":"Yu-Jia","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Center for Precision Medicine and Translational Cancer Research, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116079, Taiwan"},{"name":"Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116079, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","first-page":"e70090","article-title":"Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries","volume":"76","author":"Sung","year":"2026","journal-title":"CA Cancer J. 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