ABSTRACT Preeclampsia (PE), characterized by new‐onset hypertension and proteinuria after 20 weeks of gestation, presents substantial risks to both mother and fetus. Cuproptosis represents a newly identified form of regulated cell death; its potential association with PE pathogenesis remains unclear. We retrieved the GSE60438 dataset from the GEO database and identified 557 differentially expressed genes (DEGs) associated with PE. Weighted gene co‐expression network analysis (WGCNA) was performed, and by intersecting the DEGs with WGCNA module genes, we obtained 198 candidate PE‐related genes. KEGG and GO enrichment analyses revealed their potential biological functions, with significant enrichment in lipoic acid metabolism, the tricarboxylic acid (TCA) cycle, and components of the mitochondrial matrix. By further intersecting the DEGs, WGCNA module genes, and cuproptosis‐related genes, we identified DLD as the hub cuproptosis‐related gene in PE. GSEA further revealed its involvement in key metabolic pathways. The expression of DLD in PE and normal placental tissues was detected by qRT‐PCR and immunohistochemical staining. Loss or gain‐of‐function tests were performed to assess the effects of DLD on the proliferation, migration, and invasion of HTR‐8/SVneo cells. Concurrently, pyruvate and citrate levels were quantified with commercial kits, and intracellular ultrastructure was examined by transmission electron microscopy. Herein, we detected increased DLD in the PE placental tissues. In vitro studies showed that knockdown of DLD promoted trophoblast proliferation, migration, and invasion; conversely, overexpression of DLD showed the opposite effect. Concurrently, DLD overexpression induced metabolic dysregulation in tricarboxylic acid (TCA) cycle intermediates as well as distinct mitochondrial ultrastructural alterations. Our study demonstrated that DLD, a cuproptosis‐related gene, is significantly upregulated in PE and functionally impairs trophoblast activity, suggesting its pathogenic role may be mediated through cuproptosis.
Zheng et al. (Fri,) studied this question.