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Using high\u2010throughput drug screening in bladder cancer cells, we identified Bavachalcone (Bava) as a potent gemcitabine sensitizer. Mechanistically, Bava simultaneously targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR). It competes with transferrin (Tf) for TFRC binding, reducing cellular iron influx, and inhibits EGFR\u2010mediated phosphorylation of TFRC at tyrosine 20 (Y20). These actions disrupt mitochondria iron utilization and impairs respiration. The combination of Bava and gemcitabine synergistically inhibits the repair of gemcitabine\u2010induced DNA damage, while suppressing the iron\u2010dependent ATR\u2010CHEK1\u2010E2F1 pathway and downregulating RRM1 expression. Patient\u2010derived xenograft models confirmed the superior antitumor efficacy of the Bava\u2010gemcitabine co\u2010treatment compared to monotherapies. Clinically, elevated TFRC and RRM1 expression correlates with poor prognosis, supporting their utility as biomarkers of bladder cancer. Our study identified Bava as the first small\u2010molecule TFRC inhibitor that overcomes gemcitabine resistance through iron modulation, providing both mechanistic insights and a promising therapeutic strategy for bladder cancer.<\/jats:p>","DOI":"10.1002\/imt2.70071","type":"journal-article","created":{"date-parts":[[2025,8,17]],"date-time":"2025-08-17T09:55:04Z","timestamp":1755424504000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Bavachalcone targets transferrin receptor and sensitizes gemcitabine to affect bladder cancer progression"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3514-7765","authenticated-orcid":false,"given":"Zihao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Urology Fudan University Shanghai Cancer Center; Center; Department of Oncology, Shanghai Medical College, Fudan University Shanghai China"},{"name":"Qingdao Institute, School of Life Medicine, Department of Urology Fudan University Shanghai Cancer Center, Fudan University Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qintao","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Urology Fudan University Shanghai Cancer Center; 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