Wang Qianghua, Wang Xuegu, Fei Jiaojiao, Jiang Chuanyue, Tao Yafen, Yang Nana, Chen Huijuan, Dou Chengli, Ding Biao, Du Danli, Li Xiang
Laboratory of Department of Infectious Diseases, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
Reproductive Medicine Center, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
Front Immunol. 2025 Aug 11;16:1627057. doi: 10.3389/fimmu.2025.1627057. eCollection 2025.
Early-onset preeclampsia (EOPE) is a severe form of preeclampsia that mainly contributes to maternal and perinatal morbidity and mortality worldwide. This study aimed to systematically analyze the expression and function of ferroptosis-related gene HILPDA in EOPE placentas.
We included five transcriptomic datasets (GSE148241, GSE44711, GSE74341, GSE114691, GSE10588) downloaded from the Gene Expression Omnibus (GEO) in this study. Using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning models (LASSO, SVM-RFE, Random Forest), We identified hub genes and diagnostic biomarkers. We performed functional enrichment (GO and KEGG) and immune infiltration analysis to elucidate molecular mechanisms. Experimental validation included Western blot on clinical placental samples and siRNA-mediated knockdown in HTR-8/SVneo trophoblasts to assess migration.
We observed HILPDA upregulation and confirmed its diagnostic accuracy (AUC=0.71) in EOPE placentas. Functional analysis revealed HILPDA-associated enrichment in immune regulation (leukocyte migration, MHC complexes) and cellular processes (collagen organization, HIF-1 signaling). Through WGCNA, we identified 171 HILPDA-associated DEGs. Machine learning prioritized PART1 as diagnostic biomarkers. Immune profiling highlighted HILPDA's correlation with activated dendritic cells, neutrophils and resting mast cells. Experimentally, we confirmed HILPDA up-regulation in EOPE placentas and its critical role in suppressing trophoblast migration.
Our study establishes HILPDA as a central mechanistic regulator involved in placental immune dysregulation and trophoblast migration in EOPE pathogenesis. The identified biomarkers PART1 and HILPDA-associated pathways may offer novel diagnostic and therapeutic targets for EOPE management, which contribute to reduce maternal morbidity and prevent perinatal mortality in this catastrophic pregnancy syndrome.
早发型子痫前期（EOPE）是子痫前期的一种严重形式，在全球范围内主要导致孕产妇和围产儿发病及死亡。本研究旨在系统分析铁死亡相关基因HILPDA在EOPE胎盘组织中的表达及功能。
本研究纳入了从基因表达综合数据库（GEO）下载的5个转录组数据集（GSE148241、GSE44711、GSE74341、GSE114691、GSE10588）。通过差异表达分析、加权基因共表达网络分析（WGCNA）和机器学习模型（LASSO、SVM - RFE、随机森林），我们鉴定出了枢纽基因和诊断生物标志物。我们进行了功能富集（GO和KEGG）及免疫浸润分析以阐明分子机制。实验验证包括对临床胎盘样本进行蛋白质免疫印迹分析，以及在HTR - 8/SVneo滋养层细胞中通过小干扰RNA介导的基因敲低来评估细胞迁移。
我们观察到HILPDA在EOPE胎盘组织中上调，并证实了其诊断准确性（AUC = 0.71）。功能分析揭示了HILPDA在免疫调节（白细胞迁移、MHC复合体）和细胞过程（胶原蛋白组织、HIF - 1信号传导）方面的相关富集。通过WGCNA，我们鉴定出了171个与HILPDA相关的差异表达基因（DEG）。机器学习将PART1优先作为诊断生物标志物。免疫图谱突出了HILPDA与活化树突状细胞、中性粒细胞和静止肥大细胞的相关性。在实验中，我们证实了HILPDA在EOPE胎盘组织中的上调及其在抑制滋养层细胞迁移中的关键作用。
我们的研究确定HILPDA是参与EOPE发病机制中胎盘免疫失调和滋养层细胞迁移的核心机制调节因子。所鉴定的生物标志物PART1和与HILPDA相关的通路可能为EOPE的管理提供新的诊断和治疗靶点，这有助于降低孕产妇发病率并预防这种灾难性妊娠综合征中的围产儿死亡。
