Jiang Yi, You Qingxia, Mu Fangxiang, Xiang Shiqing, Zhang Nian
Department of Integrated TCM and Western Medicine, Southwest Hospital of Army Medical University, Chongqing 400038, China.
Department of Clinical Laboratory, Southwest Hospital of Army Medical University, Chongqing 400038, China.
J Reprod Immunol. 2025 Mar;168:104446. doi: 10.1016/j.jri.2025.104446. Epub 2025 Feb 5.
This study aims to explore whether endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) processes could be potential targets for preventive, diagnostic, and therapeutic for recurrent pregnancy loss (RPL). RPL datasets GSE165004 and GSE26787 were sourced from the GEO database, and ERS- and UPR-related gene sets were obtained from the MsigDB database. After differentially expressed genes (DEGs) identification, key genes were screened from intersecting DEGs in RPL-ERS and RPL-UPR datasets. The z-score algorithm was conducted to obtain phenotype scores. Functional enrichment and machine learning analyses were performed to assess gene function and diagnostic value evaluation. Interaction networks were conducted to investigate upstream regulated relationships of the key genes. Immune infiltration and single-cell RNA sequencing (scRNA-seq) were assessed to explore ERS and UPR functions at the cellular level. Totally 25 key genes RPL-ERS DEGs and 16 key genes RPL-UPR DEGs were identified. Among them, six key genes (NFYB, EXOSC2, UBQLN2, RNF139, DERL1, and FBXO27) were validated to show consistent expression trends in both RPL datasets. Functional enrichment highlighted their involvement in the immunity of RPL. Machine learning indicated the significant diagnostic value of these validated genes for RPL, with an accuracy rate of > 80 %. scRNA-seq analysis revealed elevated ERS and UPR expressions in monocytes/macrophages in RPL samples. In conclusion, ERS and UPR processes are associated with RPL occurrences, and were mainly upregulated in monocytes/macrophages within RPL samples. ERS and UPR processes may serve as potential targets for the prevention, diagnosis, and treatment of RPL.
本研究旨在探讨内质网应激（ERS）和未折叠蛋白反应（UPR）过程是否可能成为复发性流产（RPL）预防、诊断和治疗的潜在靶点。RPL数据集GSE165004和GSE26787来自GEO数据库，ERS和UPR相关基因集从MsigDB数据库获得。在鉴定差异表达基因（DEG）后，从RPL-ERS和RPL-UPR数据集中的交叉DEG中筛选关键基因。采用z评分算法获得表型评分。进行功能富集和机器学习分析以评估基因功能和诊断价值评估。构建相互作用网络以研究关键基因的上游调控关系。评估免疫浸润和单细胞RNA测序（scRNA-seq）以在细胞水平上探索ERS和UPR功能。共鉴定出25个RPL-ERS DEG关键基因和16个RPL-UPR DEG关键基因。其中，六个关键基因（NFYB、EXOSC2、UBQLN2、RNF139、DERL1和FBXO27）在两个RPL数据集中均表现出一致的表达趋势。功能富集突出了它们参与RPL的免疫过程。机器学习表明这些验证基因对RPL具有显著的诊断价值，准确率>80%。scRNA-seq分析显示RPL样本中单核细胞/巨噬细胞的ERS和UPR表达升高。总之，ERS和UPR过程与RPL的发生有关，且主要在RPL样本中的单核细胞/巨噬细胞中上调。ERS和UPR过程可能成为RPL预防、诊断和治疗的潜在靶点。
