Abstract
Enzalutamide, as a second-generation anti-androgen agent, has been used to treat castration-resistant prostate cancer (CRPC) or metastatic castration-sensitive prostate cancer (mCSPC). However, enzalutamide resistance inevitably developed for most treated CRPC/mCSPC, and limited effective therapies are currently available for these enzalutamide-resistant prostate cancers. In this study, we utilize our established enzalutamide-resistant prostate cancer cell lines to reveal a vulnerability of these cancer cells to GPX4-targeted ferroptosis. Interestingly, the established enzalutamide-resistant prostate cancer cells are mixed populations that predominantly exhibit stem cell-like (SCL) and neuroendocrine-like (NEL) phenotypes and may reflect cellular heterogeneity during the development of enzalutamide resistance in prostate cancer. We further demonstrated that ACSL4, a long-chain fatty acid-CoA ligase, was upregulated by the JAK/STAT pathway in enzalutamide-resistant SCL/NEL cells, thereby facilitating tumor proliferation and metastasis while increasing sensitivity to ferroptosis. To antagonize the ACSL4-conferred ferroptosis risk, SCL/NEL cells upregulated GPX4 through AP-1 transcription complex to suppress ferroptosis and thus promoted the malignant progression of SCL/NEL cells. Notably, we characterized Auranofin, an anti-rheumatoid arthritis drug, as a ferroptosis inducer for these SCL/NEL cells in vitro and in vivo by targeting AP-1 and decreasing GPX4 expression, suggesting a new application for Auranofin in treating enzalutamide-resistant stem cell-like AP-1High CRPC.
Funding
This work was supported by the National Natural Science Foundation of China (#82173131 to HH), the Science and Technology Innovation Commission of Shenzhen Municipal Government Grants (#JCYJ20240813095300002 to HH), the Guangdong Provincial Natural Science Foundation (#2023A1515010124 and #2024A1515012783 to HH), and the #G030410001 Medical Research Innovation Project.
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The Experimental Animal Welfare and Ethics Committee of the Southern University of Science and Technology approved all experimental animal procedures.
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Edited by: Professor Boyi Gan
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Zhou, Y., He, J., Zhang, H. et al. Ferroptosis vulnerability of enzalutamide resistant prostate cancer conferred by ACSL4 overexpression and GPX4 antagonism. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08906-8
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DOI: https://doi.org/10.1038/s41419-026-08906-8
