雄激素受体（AR）的抑制通过雄激素缺乏和/或抗雄激素的使用是晚期前列腺癌（PCa）的主要治疗方法。然而，大多数前列腺癌最终对这些治疗产生抗药性，表明识别导致抗药性的机制以改善患者的预后至关重要。本研究证明抗雄激素恩扎鲁胺（ENZ）短期治疗降低了前列腺癌细胞中谷胱甘肽（GSH）的产生，增加了脂质过氧化，并诱导了铁过氧化作用。一致的转录组学数据的元分析将雄激素-AR轴与与代谢有关的生物过程（包括脂质代谢）相关联。半胱氨酸转运蛋白基因SLC7A11是一个关键的AR靶点，全长AR（AR-FL）通过直接占据SLC7A11启动子和潜在增强子区域来转激活SLC7A11的转录。AR变异体（AR-Vs）优先结合SLC7A11增强子，并上调SLC7A11表达，从而使抗ENZ治疗引起的铁过氧化作用产生抗药性。然而，使用双重CBP/p300和BET抑制剂NEO2734下调AR-Vs后，这种效应被废除。这些发现揭示了铁过氧化作用的诱导是抗雄激素药物的一种抗癌机制，SLC7A11是AR-FL和AR-Vs的直接靶基因。AR-V介导的SLC7A11表达代表了将铁过氧化抗药性与PCa进展相连接的机制。

Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer (PCa). However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in PCa cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-Vs) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anti-cancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to PCa progression.