Bavachalcone targets transferrin receptor and sensitizes gemcitabine to affect bladder cancer progression
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.
Authors
- Jialin Meng (ORCID: https://orcid.org/0000-0002-4622-833X)
- Tao Feng (ORCID: https://orcid.org/0000-0001-8550-0626)
- Zihao Zhang (ORCID: https://orcid.org/0009-0007-3514-7765)
- Yijun Shen (ORCID: https://orcid.org/0000-0002-7138-1221)
- Guohai Shi
- Dalong Cao
- Shengfeng Zheng
- Wangrui Liu (ORCID: https://orcid.org/0000-0002-0459-4446)
- Qintao Ge (ORCID: https://orcid.org/0000-0001-5040-6699)
- Xi Tian (ORCID: https://orcid.org/0000-0003-1965-0647)
- Chao Tu (ORCID: https://orcid.org/0000-0001-8267-4727)
- Chenyue Yuan (ORCID: https://orcid.org/0000-0002-4124-8788)
- Yue Wang (ORCID: https://orcid.org/0000-0001-6936-5081)
- Ziliang Wang (ORCID: https://orcid.org/0000-0002-2702-5887)
- Hailiang Zhang (ORCID: https://orcid.org/0000-0001-8408-7446)
- Wei Zhang (ORCID: https://orcid.org/0000-0003-1796-0182)
- Meng Xu (ORCID: https://orcid.org/0000-0002-4470-8815)
- Wei Huang (ORCID: https://orcid.org/0000-0002-4733-0889)
- Dingwei Ye (ORCID: https://orcid.org/0000-0002-5683-0260)
- Zhongyuan Wang (ORCID: https://orcid.org/0009-0002-8553-5727)
- Mengfei Wang (ORCID: https://orcid.org/0009-0009-1924-4690)
- Ziqi Chen (ORCID: https://orcid.org/0000-0001-7494-2082)
Institutions
- Shanghai Medical College of Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- Anhui Medical University (CN)
- Renji Hospital (CN)
- Soochow University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Traditional Chinese Medicine Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
Publication Details
- Journal
- iMeta
- Published
- 2025-08-17
- DOI
- https://doi.org/10.1002/imt2.70071
- Citations
- 2
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China