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Cisplatin is the primary drug for metastatic bladder cancer chemotherapy; however, its application is limited by nephrotoxicity and resistance. Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor often overactivated in various cancers, making it an appealing drug target. Fucoxanthin, a marine carotenoid, has significant anticancer properties. This study explored Fucoxanthin\u2019s cytotoxic effects and its potential to potentiate the efficacy of Cisplatin, along with the mechanisms underlying these effects, on human bladder TCC cells. We demonstrated that Fucoxanthin is cytotoxic to bladder TCC cells by inducing apoptosis, evidenced by z-VAD-fmk-mediated annulment of Fucoxanthin\u2019s cytotoxicity. Furthermore, Fucoxanthin reduced the levels of inherent or interleukin-6-induced tyrosine 705-phosphorylated STAT3 accompanied by downregulating BCL-xL, a well-established STAT3 target. Notably, ectopic expression of STAT3-C, a dominant-active STAT3 mutant, or BCL-xL thwarted Fucoxanthin\u2019s proapoptotic and cytotoxic actions. Moreover, Fucoxanthin at subtoxic dosages enhanced the susceptibility to Cisplatin-induced apoptosis of bladder TCC cells initially resistant to Cisplatin. Remarkably, this Cisplatin-sensitizing effect of Fucoxanthin was abrogated when cells ectopically expressed STAT3-C or BCL-xL. Overall, for the first time, we proved that the proapoptotic, cytotoxic, and Cisplatin-sensitizing effects of Fucoxanthin on human bladder TCC cells are attributed to the blockade of the STAT3\/BCL-xL axis. Our findings highlight that targeting the STAT3\/BCL-xL axis is a promising strategy to eliminate bladder TCC cells and facilitate Cisplatin sensitization, and further support the potential of incorporating Fucoxanthin into Cisplatin-based chemotherapy for treating bladder cancer.<\/jats:p>","DOI":"10.3390\/md23020054","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T11:09:02Z","timestamp":1737544142000},"page":"54","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Blockade of the STAT3\/BCL-xL Axis Leads to the Cytotoxic and Cisplatin-Sensitizing Effects of Fucoxanthin, a Marine-Derived Carotenoid, on Human Bladder Urothelial Carcinoma Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Wen-Chyi","family":"Dai","sequence":"first","affiliation":[{"name":"Doctoral Program in Biotechnology Industrial Innovation and Management, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Hsuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Ching","family":"Peng","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-Ching","family":"He","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-Yu","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Tungs\u2019 Taichung MetroHarbor Hospital, Taichung 435403, Taiwan"},{"name":"Department of Rehabilitation, Jenteh Junior College of Medicine, Nursing and Management, Miaoli 356006, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3509-3713","authenticated-orcid":false,"given":"Chia-Che","family":"Chang","sequence":"additional","affiliation":[{"name":"Doctoral Program in Biotechnology Industrial Innovation and Management, National Chung Hsing University, Taichung 402202, Taiwan"},{"name":"Department of Life Sciences, National Chung Hsing University, Taichung 402202, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402202, Taiwan"},{"name":"Master Program in Precision Health, Doctoral Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung 402202, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413305, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00345-008-0357-x","article-title":"Molecular targets and targeted therapies in bladder cancer management","volume":"27","author":"Youssef","year":"2009","journal-title":"World J. 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