Bavachalcone targets TFRC and sensitizes gemcitabine to affect bladder cancer progression through the iron-dependent ATR-CHEK1-E2F1 signaling pathway

Gemcitabine resistance is a critical factor contributing to the recurrence and progression of bladder cancer. In this study, we utilized high-throughput drug screening and bladder cancer organoid models to identify Bavachalcone (Bava) as a sensitizing agent for gemcitabine, thereby inhibiting the progression of bladder cancer. Bava targets transferrin receptor (TFRC) and epidermal growth factor receptor (EGFR), competitively binding to TFRC with transferrin (Tf), which reduces the influx of iron ions and the activity of mitochondrial respiratory chain complexes. Concurrently, Bava inhibits the phosphorylation of TFRC at tyrosine 20 (Y20) by blocking EGFR phosphorylation, thereby stabilizing TFRC on the cell membrane. The combination of Bava and gemcitabine effectively inhibits the repair of DNA damage induced by gemcitabine. Additionally, Bava suppresses the iron-induced ATR-CHEK1-E2F1 signaling pathway and decreases the expression of RRM1, further sensitizing cells to gemcitabine. Studies utilizing patient-derived xenografts of bladder cancer have demonstrated that the Bava-gemcitabine combination significantly inhibits tumor progression. Correlating with clinical data, we found that TFRC and RRM1 may serve as markers of poor prognosis in bladder cancer. In summary, our research has identified specific Chinese medicine monomers that sensitize cells to gemcitabine, elucidated their direct action targets, and highlighted the role of iron ions in tumor development. This work also paves the way for novel drug design strategies that target TFRC to inhibit iron ion influx and mitigate bladder cancer progression.