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Herein, we discovered that the enhanced hypoxia-induced transforming growth factor beta induced protein (TGFBI) in bladder cancer (BLCA) promotes the establishment of a stemness loop in the tumor microenvironment, facilitating the maintenance of CSC stemness and malignant proliferation. Clinically, the upregulation of hypoxic TGFBI in BLCA correlates with malignant BLCA features and poor prognosis. Mechanically, TGFBI can stabilize the structural integrity of disulfide bonds in Cys48 and Cys77 of growth differentiation factor 15 (GDF15), leading to aberrant function activity of GDF15 and secretion. Interestingly, secreted GDF15 consequently not only further upregulates CSC-related gene expression but also induces the activation of cancer-associated fibroblasts through the transforming growth factor beta receptor type 2 (TGFBR2)\u2013transforming growth factor \u03b2 (TGF\u03b2)\u2013TGFBI self-regulatory feedback loop to promote stemness in BLCA. TGFBI knockdown or GDF15 inhibition results in a decrease in functional proteins associated with stemness maintenance, which suppresses bladder CSCs\u2019 self-renewal and effectively improves the efficacy of chemotherapy. Together, these findings demonstrate the pivotal role of TGFBI in BLCA\u2019s stemness maintenance and BLCA progression, highlighting that the inhibition of the TGFBI\/GDF15 axis is a potential therapeutic strategy for the amelioration of cancer chemotherapy.<\/jats:p>","DOI":"10.34133\/research.1134","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T02:49:46Z","timestamp":1768358986000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":3,"title":["Hypoxia-Induced TGFBI Promotes Bladder Cancer Progression by Creating a Stemness Regulation Loop through Stabilizing the Disulfide Bonds of GDF15"],"prefix":"10.34133","volume":"9","author":[{"given":"Gaojie","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozhi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, \rChongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, \rChongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuchen","family":"Li","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, \rChongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziling","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine, \rChongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Hospital of Jilin University, Changchun, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqiang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Urology, \rPeking Union Medical College, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyang","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongpeng","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-3075","authenticated-orcid":true,"given":"Jiayu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, \rFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"issue":"2","key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41585-020-00404-6","article-title":"Defining cisplatin eligibility in patients with muscle-invasive bladder cancer","volume":"18","author":"Jiang DM","year":"2021","unstructured":"Jiang DM, Gupta S, Kitchlu A, Meraz-Munoz A, North SA, Alimohamed NS, Blais N, Sridhar SS. 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