Androgen receptor-regulated ZNF419 modulates ferroptosis sensitivity via the ZDHHC20-GPX4 pathway in prostate cancer.
8 affiliations
- 1Department of Urology, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China; Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
- 2Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
- 3China Medical University, Shenyang, Liaoning, China.
- 4Department of Pathology, The College of Basic Medical Sciences and the First Hospital of China Medical University, Shenyang, Liaoning, China.
- 5Departments of Pathology & Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, NY, USA.
- 6Department of Urology, The First Hospital of China Medical University, Shenyang, 110001, China. Electronic address: [email protected].
- 7Department of Urology, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China. Electronic address: [email protected].
- 8Department of Pathology, The College of Basic Medical Sciences and the First Hospital of China Medical University, Shenyang, Liaoning, China. Electronic address: [email protected].
Abstract
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been recognized as a crucial determinant of therapeutic response in prostate cancer (PCa). However, how androgen receptor (AR) signaling regulates ferroptotic susceptibility remains poorly understood. Here, we identify ZNF419, a previously uncharacterized zinc finger protein, as an AR-regulated factor associated with reduced ferroptosis susceptibility in PCa cells. Transcriptomic profiling and functional validation revealed that ZNF419 expression is markedly elevated in PCa and correlates with poor clinical outcome. Promoter-proximal AR occupancy was detected at predicted ARE-containing regions of the ZNF419 locus and contributed to ZNF419 promoter activation in reporter assays, whereas enzalutamide treatment or AR knockdown reduced ZNF419 expression and increased ferroptosis-associated vulnerability. Mechanistically, ZNF419 promotes ZDHHC20 expression and is associated with activation of a candidate downstream enhancer region. ZDHHC20, a palmitoyltransferase, contributes to GPX4 palmitoylation-associated stabilization and limits ubiquitin-mediated proteasomal degradation of GPX4. Pharmacological interference with palmitoylation attenuates ZNF419-associated GPX4 stabilization, whereas ZDHHC20 restoration partially reverses the increased ferroptosis-associated vulnerability of ZNF419-deficient cells. Collectively, our findings support a previously unrecognized AR-associated ZNF419-ZDHHC20-GPX4 regulatory axis that links AR activity to ferroptosis-associated vulnerability. These findings provide a rationale for further investigating whether modulation of this pathway may influence responses to AR-targeted therapy in advanced PCa.
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BibTeX
@article{hou2026androgen,
title = {{Androgen receptor-regulated ZNF419 modulates ferroptosis sensitivity via the ZDHHC20-GPX4 pathway in prostate cancer.}},
author = {Yuanxiang Hou and Wenyan Zhao and Jingyi Liu and Ruiping Tang and Tong Deng and Huaiyu Zhu and Hiroshi Miyamoto and Yuyan Zhu and Ming Sun and Guiyang Jiang},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104433},
url = {https://europepmc.org/article/MED/42858533},
note = {CC BY},
}
RIS
TY - JOUR
TI - Androgen receptor-regulated ZNF419 modulates ferroptosis sensitivity via the ZDHHC20-GPX4 pathway in prostate cancer.
AU - Yuanxiang Hou
AU - Wenyan Zhao
AU - Jingyi Liu
AU - Ruiping Tang
AU - Tong Deng
AU - Huaiyu Zhu
AU - Hiroshi Miyamoto
AU - Yuyan Zhu
AU - Ming Sun
AU - Guiyang Jiang
PY - 2026
DA - 2026/10/08
JO - Redox biology
DO - 10.1016/j.redox.2026.104433
UR - https://europepmc.org/article/MED/42858533
AB - Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been recognized as a crucial determinant of therapeutic response in prostate cancer (PCa). However, how androgen receptor (AR) signaling regulates ferroptotic susceptibility remains poorly understood. Here, we identify ZNF419, a previously uncharacterized zinc finger protein, as an AR-regulated factor associated with reduced ferroptosis susceptibility in PCa cells. Transcriptomic profiling and functional validation revealed that ZNF419 expression is markedly elevated in PCa and correlates with poor clinical outcome. Promoter-proximal AR occupancy was detected at predicted ARE-containing regions of the ZNF419 locus and contributed to ZNF419 promoter activation in reporter assays, whereas enzalutamide treatment or AR knockdown reduced ZNF419 expression and increased ferroptosis-associated vulnerability. Mechanistically, ZNF419 promotes ZDHHC20 expression and is associated with activation of a candidate downstream enhancer region. ZDHHC20, a palmitoyltransferase, contributes to GPX4 palmitoylation-associated stabilization and limits ubiquitin-mediated proteasomal degradation of GPX4. Pharmacological interference with palmitoylation attenuates ZNF419-associated GPX4 stabilization, whereas ZDHHC20 restoration partially reverses the increased ferroptosis-associated vulnerability of ZNF419-deficient cells. Collectively, our findings support a previously unrecognized AR-associated ZNF419-ZDHHC20-GPX4 regulatory axis that links AR activity to ferroptosis-associated vulnerability. These findings provide a rationale for further investigating whether modulation of this pathway may influence responses to AR-targeted therapy in advanced PCa.
SN - 2213-2317
ER -