WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer
Abstract Chemoresistance continues to pose a significant challenge in managing colorectal cancer (CRC), resulting in unfavorable outcomes for patients. Recent findings indicate that ferroptosis, an innovative type of regulated cell death, might influence chemoresistance. In this research, we explore...
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2025-03-01
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| Online Access: | https://doi.org/10.1186/s10020-025-01151-3 |
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| author | Yang Wang Dachuan Qi Guijie Ge Ning Cao Xiangdong Liu Na Zhu Feng Li Xiang Huang Kui Yu Jinzhou Zheng Daoheng Wang Wenyan Yao Lili Chen Ziyang Dong |
| author_facet | Yang Wang Dachuan Qi Guijie Ge Ning Cao Xiangdong Liu Na Zhu Feng Li Xiang Huang Kui Yu Jinzhou Zheng Daoheng Wang Wenyan Yao Lili Chen Ziyang Dong |
| author_sort | Yang Wang |
| collection | DOAJ |
| description | Abstract Chemoresistance continues to pose a significant challenge in managing colorectal cancer (CRC), resulting in unfavorable outcomes for patients. Recent findings indicate that ferroptosis, an innovative type of regulated cell death, might influence chemoresistance. In this research, we explored how WW domain-binding protein 1 (WBP1) affects mitochondrial function, cell growth, ferroptosis, and chemoresistance in CRC cells. By employing both genetic and pharmacological methods, we found that WBP1 is essential for maintaining mitochondrial respiration in CRC cells. WBP1 depletion impaired mitochondrial function, leading to reduced cell proliferation and increased ferroptosis. Exogenous mitochondria from wild-type cells restored mitochondrial function, cell proliferation, and suppressed ferroptosis in WBP1-deficient cells, indicating that mitochondrial function acts downstream of WBP1. Importantly, we demonstrated that targeting WBP1 or its mediated mitochondrial function sensitized chemoresistant CRC cells to 5-fluorouracil and oxaliplatin by inducing ferroptosis. Furthermore, we analyzed transcriptome data from CRC patients, which indicated that increased WBP1 expression correlated with poor outcomes for patients receiving chemotherapy, thus highlighting the clinical significance of our observations. Collectively, our results pinpoint WBP1 as a significant modulator of mitochondrial function and ferroptosis in CRC cells and imply that targeting WBP1 may represent a viable approach to tackling chemoresistance. These insights offer a deeper understanding of the molecular pathways underlying CRC chemoresistance and may guide the development of new treatment options. |
| format | Article |
| id | doaj-art-895689e9bdda48e49f352b60ba24281a |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-895689e9bdda48e49f352b60ba24281a2025-08-20T02:56:16ZengBMCMolecular Medicine1528-36582025-03-0131111610.1186/s10020-025-01151-3WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancerYang Wang0Dachuan Qi1Guijie Ge2Ning Cao3Xiangdong Liu4Na Zhu5Feng Li6Xiang Huang7Kui Yu8Jinzhou Zheng9Daoheng Wang10Wenyan Yao11Lili Chen12Ziyang Dong13Department of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineSchool of Clinical Medicine, Shandong Second Medical UniversityMedical Center of Gastrointestinal Surgery, Weifang People’s HospitalDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of General Surgery, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Pharmacy, Weifang People’s HospitalAbstract Chemoresistance continues to pose a significant challenge in managing colorectal cancer (CRC), resulting in unfavorable outcomes for patients. Recent findings indicate that ferroptosis, an innovative type of regulated cell death, might influence chemoresistance. In this research, we explored how WW domain-binding protein 1 (WBP1) affects mitochondrial function, cell growth, ferroptosis, and chemoresistance in CRC cells. By employing both genetic and pharmacological methods, we found that WBP1 is essential for maintaining mitochondrial respiration in CRC cells. WBP1 depletion impaired mitochondrial function, leading to reduced cell proliferation and increased ferroptosis. Exogenous mitochondria from wild-type cells restored mitochondrial function, cell proliferation, and suppressed ferroptosis in WBP1-deficient cells, indicating that mitochondrial function acts downstream of WBP1. Importantly, we demonstrated that targeting WBP1 or its mediated mitochondrial function sensitized chemoresistant CRC cells to 5-fluorouracil and oxaliplatin by inducing ferroptosis. Furthermore, we analyzed transcriptome data from CRC patients, which indicated that increased WBP1 expression correlated with poor outcomes for patients receiving chemotherapy, thus highlighting the clinical significance of our observations. Collectively, our results pinpoint WBP1 as a significant modulator of mitochondrial function and ferroptosis in CRC cells and imply that targeting WBP1 may represent a viable approach to tackling chemoresistance. These insights offer a deeper understanding of the molecular pathways underlying CRC chemoresistance and may guide the development of new treatment options.https://doi.org/10.1186/s10020-025-01151-3Colorectal cancerMitochondrial functionChemoresistanceFerroptosis |
| spellingShingle | Yang Wang Dachuan Qi Guijie Ge Ning Cao Xiangdong Liu Na Zhu Feng Li Xiang Huang Kui Yu Jinzhou Zheng Daoheng Wang Wenyan Yao Lili Chen Ziyang Dong WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer Molecular Medicine Colorectal cancer Mitochondrial function Chemoresistance Ferroptosis |
| title | WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer |
| title_full | WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer |
| title_fullStr | WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer |
| title_full_unstemmed | WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer |
| title_short | WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer |
| title_sort | wbp1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer |
| topic | Colorectal cancer Mitochondrial function Chemoresistance Ferroptosis |
| url | https://doi.org/10.1186/s10020-025-01151-3 |
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