Disruption of the AR/ZNF217/PROM2 axis sensitizes prostate cancer to ferroptosis and enzalutamide therapy
9 affiliations
- 1Department of Urology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- 2Liaoning Provincial Key Laboratory of Urological Digital Precision Diagnosis and Treatment, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- 3Liaoning Engineering Research Center of Integrated Precision Diagnosis and Treatment Technology for Urological Cancer, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- 4Dalian Key Laboratory of Prostate Cancer Research, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- 5Pharmaceutical Research Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- 6College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
- 7Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, China
- 8Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- 9College of Pharmacy, Dalian Medical University, Dalian, China
Abstract
Dysregulation of androgen receptor (AR) signaling is a key molecular driver of prostate cancer development and its transition to castration-resistant disease. Although emerging evidence indicates that AR may influence ferroptosis by modulating lipid peroxidation and antioxidant systems, the complete transcriptional network through which AR regulates ferroptosis remains incompletely defined. In this study, we identify the transcription factor ZNF217 as a direct downstream target of AR, which is aberrantly upregulated in prostate cancer and associated with poor clinical outcomes. ZNF217 enhances the transcriptional activity of its downstream effector PROM2, thereby suppressing ferroptosis and promoting cell survival. Functional assays demonstrate that ZNF217 silencing markedly amplifies ferroptotic features, whereas ZNF217 overexpression partially alleviates ferroptosis-induced cellular damage. Building on these findings, we established a drug screening system based on ZNF217 expression and identified the compound RSL3 from a panel of 13 ferroptosis inducers, which potently suppresses ZNF217 expression. Further investigations revealed that combined treatment with RSL3 and the AR antagonist enzalutamide produced a synergistic antitumor response in cellular and animal models, accompanied by marked attenuation of AR/ZNF217/PROM2 pathway activity and reduced tumor burden. Collectively, these findings identify AR/ZNF217/PROM2 signaling as a central determinant of ferroptotic vulnerability in prostate cancer and suggest that targeting this pathway may enhance sensitivity to AR inhibition, providing a molecular rationale for combination therapy in castration-resistant prostate cancer.
Related
- Cost-effectiveness of adding enzalutamide vs standard non-steroidal antiandrogen drugs for patients with metastatic hormone-sensitive prostate cancer undergoing standard first-line therapy: a within-trial, secondary end-point analysis of the ENZAMET phase 3, international randomized trial (ANZUP 1304)
- Skin‐Related Adverse Events in Patients Treated With Apalutamide Versus Enzalutamide for Prostate Cancer: A Japanese Real‐World Database Study (A Retrospective Cohort Study)
- Real‐World Overall Survival With Abiraterone Acetate and Enzalutamide in Patients With Chemotherapy‐Naïve Metastatic Castration‐Resistant Prostate Cancer From the Flatiron Electronic Health Records Database
- IGF1R Induces ROS Formation in Mitochondria via MICU1 Leads to the Enzalutamide Resistance in Prostate Cancer
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BibTeX
@article{hao2026disruption,
title = {{Disruption of the AR/ZNF217/PROM2 axis sensitizes prostate cancer to ferroptosis and enzalutamide therapy}},
author = {Wenjun Hao and Peng Liang and Wanglong Zheng and Minglu Sheng and Yulin Peng and Xiang Gao and Haolin Zhao and Yuyan Zhu and Yanlong Wang and Bo Fan and Zhihong Dai and Xu Sun and Liang Wang and Huan Qi and Ying Wang and Yan Wang and Zhenlong Yu and Zhiyu Liu},
journal = {Oncogenesis},
year = {2026},
month = aug,
doi = {10.1038/s41389-026-00649-7},
url = {https://doi.org/10.1038/s41389-026-00649-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Disruption of the AR/ZNF217/PROM2 axis sensitizes prostate cancer to ferroptosis and enzalutamide therapy
AU - Wenjun Hao
AU - Peng Liang
AU - Wanglong Zheng
AU - Minglu Sheng
AU - Yulin Peng
AU - Xiang Gao
AU - Haolin Zhao
AU - Yuyan Zhu
AU - Yanlong Wang
AU - Bo Fan
AU - Zhihong Dai
AU - Xu Sun
AU - Liang Wang
AU - Huan Qi
AU - Ying Wang
AU - Yan Wang
AU - Zhenlong Yu
AU - Zhiyu Liu
PY - 2026
DA - 2026/08/11
JO - Oncogenesis
DO - 10.1038/s41389-026-00649-7
UR - https://doi.org/10.1038/s41389-026-00649-7
AB - Dysregulation of androgen receptor (AR) signaling is a key molecular driver of prostate cancer development and its transition to castration-resistant disease. Although emerging evidence indicates that AR may influence ferroptosis by modulating lipid peroxidation and antioxidant systems, the complete transcriptional network through which AR regulates ferroptosis remains incompletely defined. In this study, we identify the transcription factor ZNF217 as a direct downstream target of AR, which is aberrantly upregulated in prostate cancer and associated with poor clinical outcomes. ZNF217 enhances the transcriptional activity of its downstream effector PROM2, thereby suppressing ferroptosis and promoting cell survival. Functional assays demonstrate that ZNF217 silencing markedly amplifies ferroptotic features, whereas ZNF217 overexpression partially alleviates ferroptosis-induced cellular damage. Building on these findings, we established a drug screening system based on ZNF217 expression and identified the compound RSL3 from a panel of 13 ferroptosis inducers, which potently suppresses ZNF217 expression. Further investigations revealed that combined treatment with RSL3 and the AR antagonist enzalutamide produced a synergistic antitumor response in cellular and animal models, accompanied by marked attenuation of AR/ZNF217/PROM2 pathway activity and reduced tumor burden. Collectively, these findings identify AR/ZNF217/PROM2 signaling as a central determinant of ferroptotic vulnerability in prostate cancer and suggest that targeting this pathway may enhance sensitivity to AR inhibition, providing a molecular rationale for combination therapy in castration-resistant prostate cancer.
SN - 2157-9024
ER -