Bavachalcone targets transferrin receptor and sensitizes gemcitabine to affect bladder cancer progression

Abstract Gemcitabine resistance drives bladder cancer recurrence and progression. Using high‐throughput 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‐mediated 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‐induced DNA damage, while suppressing the iron‐dependent ATR‐CHEK1‐E2F1 pathway and downregulating RRM1 expression. Patient‐derived xenograft models confirmed the superior antitumor efficacy of the Bava‐gemcitabine co‐treatment 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‐molecule TFRC inhibitor that overcomes gemcitabine resistance through iron modulation, providing both mechanistic insights and a promising therapeutic strategy for bladder cancer.