卵巢癌（OVC）是妇女中最致命和最侵袭性的肿瘤之一，近年来发病率逐渐增加。Cuproptosis是一种新发现的程序性细胞死亡方式，由细胞内铜介导的脂脯酰化蛋白聚集和蛋白质毒性应激引起。然而，Cuproptosis相关特征在OVC中的作用仍不明确。本研究使用GSE154600的单细胞测序数据和TCGA数据库上378例OVC患者的批量转录组数据，以及GSE140082的379例OVC患者和GSE53963的173例卵巢患者的RNA-seq和临床数据。通过计算PROGENy得分来评估与肿瘤相关的通路。基于Cuproptosis通路的基因集富集分析（GSEA），将单个细胞分为cuproptosis高和cuproptosis低两组。筛选出两组之间的差异表达基因（DEGs），并基于单变量Cox回归分析鉴定出47个与预后相关的基因。使用Randomforest构建预后模型。使用ssGSEA和xCell算法进行免疫浸润分析。通过体外和体内实验进行功能验证。识别出包括成纤维细胞、T细胞、髓系、上皮细胞、内皮细胞和B细胞群体在内的六个主要细胞群体。PROGENy得分揭示了T细胞和B细胞中PI3K通路的显著活化，内皮细胞和成纤维细胞中TGF-β通路的激活。从鉴定出的47个与预后相关的基因中选择TIMM8B、COX8A、SSR4、HIGD2A、WASF2、PRDX5和CLDN4构建预后模型。此外，cuproptosis高组和cuproptosis低组在模型基因的表达水平、免疫细胞浸润和对六种潜在药物候选者的敏感性方面存在显著差异。功能实验证实WASF2与cuproptotic抗性有关，促进癌细胞增殖和对铂类药物的抵抗，其高表达与OVC患者预后不良相关。识别出具有临床意义的与cuproptosis相关的预后模型，能够准确预测OVC患者的预后和免疫特征。作为预测模型中与cuproptosis相关的基因之一，WASF2促进了OVC细胞的增殖和铂类抗药性，并导致预后不良。版权所有 ©2023 Elsevier Inc.

Ovarian cancer (OVC) is one of the deadliest and most aggressive tumors in women, with an increasing incidence in recent years. Cuproptosis, a newly discovered type of programmed cell death, is caused by intracellular copper-mediated lipoylated protein aggregation and proteotoxic stress. However, the role of cuproptosis-related features in OVC remains elusive.The single-cell sequencing data from GSE154600 and bulk transcriptome data of 378 OVC patients from TCGA database. The RNA-seq and clinical data of 379 OVC patients in GSE140082 and 173 OV patients in GSE53963. The PROGENy score was calculated to assess tumor-associated pathways. Based on gene set enrichment analysis (GSEA) of the cuproptosis pathway, the single cells were divided into the cuproptosishigh and cuproptosislow groups. The differentially expressed genes (DEGs) between the two groups were screened, and 47 prognosis-related genes were identified based on univariate cox regression analysis. Randomforest was used to construct a prognostic model. Immuno-infiltration analysis was performed using ssGSEA and xCell algorithms. In vitro and in vivo experiments were used for functional verification.Six major cell populations was identified, including fibroblast, T cell, myeloid, epithelial cell, endothelial cell, and B cell populations. The PROGENy score which revealed significant activation of the PI3K pathway in T and B cells, and activation of the TGF-β pathway in endothelial cells and fibroblasts. TIMM8B, COX8A, SSR4, HIGD2A, WASF2, PRDX5 and CLDN4 were selected to construct a prognostic model from the identified 47 prognosis-related genes. Furthermore, the cuproptosishigh and cuproptosislow groups showed significant differences in the expression levels of the model genes, immune cell infiltration, and sensitivity to six potential drug candidates. The functional experiments showed that WASF2 is associated with cuproptotic resistance and promotes cancer cell proliferation and resistance to platinum, and its high expression is associated with poor prognosis of OVC patients.A clinically significant cuproptosis-related prognostic model was identified which can accurately predict the prognosis and immune characteristics of OVC patients. WASF2, one of the cuproptosis-related gene in the risk model, promotes the proliferation and platinum resistance of OVC cells, and leads poor prognosis.Copyright © 2023. Published by Elsevier Inc.