前列腺癌（PCA）是一种常见的恶性泌尿生殖肿瘤，严重影响患者的生存率。铜依赖性程序性细胞死亡机制——铜脱落黄嘌呤-核酸酶（cuproptosis）在PCA的肿瘤发展、疗法抵抗和免疫微环境调节中发挥着重要作用。然而，针对前列腺癌的cuproptosis研究仍处于早期阶段。使用公开的TCGA和GEO数据集，我们首先获取了PCA患者的转录组和临床信息。识别了与cuproptosis相关的基因（CRG）表达，并基于LASSO-COX方法建立了一个预测模型。根据Kaplan-Meier方法评估了该模型的预测性能。使用GEO数据集，我们进一步确认了模型中关键基因的水平。根据肿瘤免疫功能受损和排斥（TIDE）评分预测肿瘤对免疫检查点（ICP）抑制剂的响应。利用癌症药物敏感性基因组学（GDSC）预测肿瘤细胞的药物敏感性，而使用基因集变异分析（GSVA）分析与cuproptosis特征相关的富集通路。随后，验证了PDHA1基因在PCA中的功能。基于五个与cuproptosis相关的基因（ATP7B、DBT、LIPT1、GCSH、PDHA1）建立了预测风险模型。低风险组的无进展生存期明显长于高风险组，并展现出对ICB治疗的更好响应。此外，根据回归分析的结果，PDHA1在PCA的病理过程中非常重要，并进行了外部数据集的验证。PCA高表达PDHA1的患者不仅具有较短的PFS，而且很少从ICB治疗中获益，还不太容易对多种靶向治疗药物做出反应。在初步的研究中，PDHA1 knockdown明显降低了PCA细胞的增殖和侵袭能力。本研究建立了一种基于cuproptosis相关基因的前列腺癌预测模型，该模型可以准确预测PCA患者的预后，有益于个体化治疗，并可帮助临床医生为PCA患者做出临床决策。此外，我们的数据显示，PDHA1在调节免疫治疗和其他靶向治疗的敏感性的同时促进了PCA细胞的增殖和侵袭，是PCA治疗的重要靶点。本研究符合癌症研究标准，语言流畅，符合本国语言标准。翻译版权 © 2023 Elsevier Inc.

Prostate cancer (PCA) is a common malignant genitourinary tumor that significantly impacts patient survival. Cuproptosis, a copper-dependent programmed cell death mechanism, plays a vital role in tumor development, therapy resistance, and immune microenvironment regulation in PCA. However, research on cuproptosis in prostate cancer is still in its early stages.Using the publicly available datasets TCGA and GEO, we first acquired the transcriptome and clinical information of PCA patients. The expression of cuprotosis-related genes (CRG) was identified and a prediction model was established based on LASSO-COX method. The predictive performance of this model was evaluated based on Kaplan-Meier method. Using GEO datasets, we further confirmed the critical genes level in the model. Tumor responses to immune checkpoint (ICP) inhibitors were predicted based on Tumor Immune Dysfunction and Exclusion (TIDE) score. The Genomics of Drug Sensitivity in Cancer (GDSC) was utilized to forecast drug sensitivity in cancer cells, whereas the GSVA was employed to analyze enriched pathways related to the cuproptosis signature. Subsequently, the function of PDHA1 gene in PCA was verified.A predictive risk model on basis of five cuproptosis-related genes (ATP7B, DBT, LIPT1, GCSH, PDHA1) were established. The progression free survival of low-risk group was obviously longer than the high-risk group, and exhibit better response to ICB therapy.Furthermore,PDHA1 is very important in the pathological process of PCA according to regressions analysis result, and the validation of external data sets were conducted. High PDHA1 expression patients with PCA not only had a shorter PFS and were less likely to benefit from ICB treatment, but they were also less responsive to multiple targeted therapeutic drugs. In preliminary research, PDHA1 knockdown significantly decreased the proliferation and invasion of PCA cells.This study established a novel cuproptosis-related gene-based prostate cancer prediction model that accurately predicts the prognosis of PCA patients. The model benefits individualized therapy and can assist clinicians in making clinical decisions for PCA patients. Furthermore, our data show that PDHA1 promotes PCA cell proliferation and invasion while modulating the susceptibility to immunotherapy and other targeted therapies. PDHA1 can be regarded as an important target for PCA therapy. This study conforms to the standards of cancer research and is linguistically fluent and meets native language standards.Copyright © 2023. Published by Elsevier Inc.