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.
Objective This study aims to explore the clinical characteristics, genetic etiology, and individualized treatment strategies of patients with PCOS complicated by oocyte maturation disorders caused by novel compound heterozygous variants of the PATL2 gene, and to expand the mutation and phenotypic spectrum of the PATL2 gene. Methods Clinical data and two cycles of controlled ovarian hyperstimulation (COH) were collected from a 34-year-old patient with primary infertility and PMOS. Genetic analysis was performed using whole-exome sequencing (WES), and variant pathogenicity was predicted by bioinformatics tools. An individualized COH protocol was designed and implemented based on the genetic diagnosis. Results The patient had 8 years of primary infertility. In the first cycle, 10 oocytes were retrieved after COH with an antagonist protocol, all arrested at the germinal vesicle (GV) stage. WES revealed compound heterozygous variants in the PATL2 gene (OMIM: 617743): NM_001145112.1: c.1225-2A > G (splice-site variant) and c.1382 T > C (p.Leu461Pro, missense variant), consistent with autosomal recessive inheritance. Both variants were predicted to be deleterious, and c.1382 T > C was a novel unreported variant. In the second cycle, a long follicular protocol, delayed trigger, segmented oocyte retrieval, and indomethacin for spontaneous ovulation prevention were applied. A total of 24 oocytes were retrieved; however, all remained arrested at the GV stage after in vitro culture, and no mature oocytes were obtained. Conclusion Compound heterozygous variants c.1225-2A > G and c.1382 T > C in PATL2 are the core genetic cause of GV-stage oocyte arrest in this patient. GV arrest caused by PATL2 defects cannot be overcome by conventional or optimized IVF protocols even with individualized COH. WES provides critical evidence for etiological clarification, avoidance of ineffective treatment, and genetic counseling. Donor-oocyte IVF remains the ultimate effective strategy for pregnancy in such patients.
Xiaoxia Song, Lei Yan, Yiwen Zhang et al.· Frontiers in Medicine· 0 citations