AR-targeted therapies sensitize prostate cancer to cuproptosis by transcriptionally activating <i>FDX1</i>
accumulation, destabilizes Fe-S cluster proteins, and disrupts mitochondrial metabolism, establishing a procuproptotic state. Functionally, combining AR antagonists with copper ionophores synergistically induces cuproptosis and potently suppresses tumor growth in AR-positive prostate cancer cells, three-dimensional (3D) spheroids, patient-derived organoids, and xenograft models, with minimal systemic toxicity. This synergy is abolished by FDX1 loss or copper chelation, confirming dependence on AR-FDX1 axis activation. Together, these findings uncover FDX1 as a mechanistic effector of AR pathway inhibition and propose a well-tolerated combination strategy that exploits cuproptosis to improve therapeutic responses in prostate cancer.
Authors
- Yuang Wei (ORCID: https://orcid.org/0000-0001-6282-1136)
- Siliang Wang (ORCID: https://orcid.org/0000-0003-1228-869X)
- Fuwen Yuan (ORCID: https://orcid.org/0000-0001-5764-2504)
- Qianqian Zhou (ORCID: https://orcid.org/0009-0001-7478-2477)
- Lingfan Xu (ORCID: https://orcid.org/0000-0003-2465-241X)
- Yanhua Chen (ORCID: https://orcid.org/0000-0002-4514-9410)
- Fanchen Wu
- Xuehui Li
- Shan Lin
- Dongliang Xu
- Chuang Xie
- Xiaowen Song
- Xinyi Xu
Institutions
- Anhui Medical University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Yueyang Hospital (CN)
- Shanghai Traditional Chinese Medicine Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Shuguang Hospital (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-05-01
- DOI
- https://doi.org/10.1073/pnas.2534978123
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China