前列腺癌 (PCa) 是一种雄激素依赖性疾病，其中去势抵抗性前列腺癌 (CRPC) 已处于晚期，不再对雄激素剥夺疗法 (ADT) 产生反应。越来越多的证据表明，糖皮质激素受体 (GR) 通过绕过雄激素受体 (AR) 阻断，赋予 CRPC 患者对 ADT 的抵抗力。 GR作为CRPC的新型治疗靶点，引起了全世界的广泛关注。这项研究利用公开的 CRPC 单细胞数据的生物信息学分析来开发一致的糖皮质激素相关特征 (Glu-sig)，可作为无复发生存的独立预测因子。我们的结果显示，该签名在七个可公开访问的数据集和一个内部队列中表现出一致且强大的性能。此外，我们的研究结果表明，Glu-sig 中的甘油-3-磷酸脱氢酶 1 (GPD1) 可以通过介导细胞周期途径显着促进 CRPC 进展。此外，GPD1被证明受到GR的调节，GR拮抗剂米非司酮增强了GPD1在CRPC细胞中的抗肿瘤作用。从机制上讲，靶向 GPD1 诱导 1-磷酸鞘氨醇 (S1P) 的产生并增强组蛋白乙酰化，从而诱导参与细胞周期调节的 p21 转录。总之，Glu-sig 可以作为一种强大且有前途的工具来改善 PCa 患者的临床结果，而调节促进肿瘤生长的 GR/GPD1 轴可能是延缓 CRPC 进展的一种有前途的方法。版权所有 © 2024 Elsevier B.V. All保留权利。

Prostate cancer (PCa) is an androgen-dependent disease, with castration-resistant prostate cancer (CRPC) being an advanced stage that no longer responds to androgen deprivation therapy (ADT). Mounting evidence suggests that glucocorticoid receptors (GR) confer resistance to ADT in CRPC patients by bypassing androgen receptor (AR) blockade. GR, as a novel therapeutic target in CRPC, has attracted substantial attention worldwide. This study utilized bioinformatic analysis of publicly available CRPC single-cell data to develop a consensus glucocorticoid-related signature (Glu-sig) that can serve as an independent predictor for relapse-free survival. Our results revealed that the signature demonstrated consistent and robust performance across seven publicly accessible datasets and an internal cohort. Furthermore, our findings demonstrated that glycerol-3-phosphate dehydrogenase 1 (GPD1) in Glu-sig can significantly promote CRPC progression by mediating the cell cycle pathway. Additionally, GPD1 was shown to be regulated by GR, with the GR antagonist mifepristone enhancing the anti-tumorigenic effects of GPD1 in CRPC cells. Mechanistically, targeting GPD1 induced the production of sphingosine 1-phosphate (S1P) and enhanced histone acetylation, thereby inducing the transcription of p21 that involved in cell cycle regulation. In conclusion, Glu-sig could serve as a robust and promising tool to improve the clinical outcomes of PCa patients, and modulating the GR/GPD1 axis that promotes tumor growth may be a promising approach for delaying CRPC progression.Copyright © 2024 Elsevier B.V. All rights reserved.