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
{"title":"WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer.","authors":"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","doi":"10.1186/s10020-025-01151-3","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"93"},"PeriodicalIF":6.0000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10020-025-01151-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.