解析子宫内膜异位症中内质网应激与免疫浸润的分子串扰

Deciphering the Molecular Crosstalk of Endoplasmic Reticulum Stress and Immune Infiltration in Endometriosis.

作者信息

Ma Yuan, Ha Chunfang, Li Ruyue, Zhang Ruiqi, Li Min

机构信息

Ningxia Medical University, Yinchuan, China.

General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.

出版信息

Am J Reprod Immunol. 2025 May;93(5):e70092. doi: 10.1111/aji.70092.

DOI:10.1111/aji.70092

PMID:40371728

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12079719/

Abstract

BACKGROUND

Endometriosis (EMs), characterized by ectopic endometrial growth causing infertility. Endoplasmic reticulum stress (ERS) is an important cellular defense mechanism. However, the correlation between ERS and EMs remains unclear. We aimed to investigate the relationship between them, identify biomarkers, and offer new insights into the treatment of EMs.

METHODS

Two RNA expression datasets (GSE120103 and GSE25628) related to EMs in Homo sapiens were used to identify ERS-differentially expressed genes (ERS-DEGs). Protein-protein interaction (PPI) networks and CytoHubba (Cytoscape) identified ERS-associated HUB genes, with receiver operating characteristic curves (ROC) evaluating diagnostic value. Constructed mRNA-microRNA (miRNA)/RNA-transcription factor (TF) interaction networks and performed ssGSEA to compare immune infiltration between EMs patients and controls. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), and immunohistochemistry (IHC) were performed to assess potential biomarker levels.

RESULTS

Thirty-three ERS-DEGs were identified, with nine HUB genes (HSPA5, XBP1, HSP90B1, DNAJC3, PDIA3, PDIA6, PDIA4, HERPUD1, and MANF) demonstrating diagnostic efficacy (AUC > 0.7). Furthermore, immune infiltration revealed a significant relationship between immune cell abundance and HUB gene expression. Experimental validation confirmed the consistency of four biomarkers (HSPA5, HSP90B1, PDIA6, and HERPUD1). Regulatory network analysis identified 62 miRNAs and 44 TFs interacting with HUB genes, suggesting a multifactorial immunometabolic axis.

CONCLUSIONS

We identified four biomarkers (HSPA5, HSP90B1, PDIA6, and HERPUD1) associated with ERS that offer new insights into the detection and treatment of EMs. Our findings indicate an abnormal response to ERS and immune system infiltration contribute to the progression of EMs.

摘要

背景

子宫内膜异位症（EMs）以异位子宫内膜生长导致不孕为特征。内质网应激（ERS）是一种重要的细胞防御机制。然而，ERS与EMs之间的相关性仍不清楚。我们旨在研究它们之间的关系，确定生物标志物，并为EMs的治疗提供新的见解。

方法

使用两个人类与EMs相关的RNA表达数据集（GSE120103和GSE25628）来鉴定ERS差异表达基因（ERS-DEGs）。蛋白质-蛋白质相互作用（PPI）网络和CytoHubba（Cytoscape）鉴定了与ERS相关的枢纽基因，并用受试者工作特征曲线（ROC）评估诊断价值。构建mRNA-微小RNA（miRNA）/RNA-转录因子（TF）相互作用网络，并进行单样本基因集富集分析（ssGSEA）以比较EMs患者和对照组之间的免疫浸润情况。进行实时定量聚合酶链反应（RT-qPCR）、蛋白质免疫印迹法（WB）和免疫组织化学（IHC）以评估潜在生物标志物的水平。

结果

鉴定出33个ERS-DEGs，其中9个枢纽基因（HSPA5、XBP1、HSP90B1、DNAJC3、PDIA3、PDIA6、PDIA4、HERPUD1和MANF）显示出诊断效能（曲线下面积>0.7）。此外，免疫浸润揭示了免疫细胞丰度与枢纽基因表达之间的显著关系。实验验证证实了四种生物标志物（HSPA5、HSP90B1、PDIA6和HERPUD1）的一致性。调控网络分析确定了62个miRNA和44个与枢纽基因相互作用的TF，提示存在一个多因素免疫代谢轴。