Immune–coagulation activation and mitochondrial shape the transcriptomic landscape of gestational diabetes mellitus and highlight SERPINE1-associated endothelial stress

Introduction Gestational diabetes mellitus (GDM) is associated with placental dysfunction, but the molecular programs linking inflammatory, coagulation-related, and metabolic abnormalities remain incompletely defined. We investigated the serum transcriptomic landscape of GDM and evaluated whether endothelial glucolipotoxic stress could recapitulate key disease-associated signatures. Methods Serum samples from five women with GDM and five normoglycemic controls were subjected to RNA sequencing. Differentially expressed genes were analyzed by overrepresentation analysis, and protein–protein interaction network construction. To validate candidate pathways, human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein. Serpin family E member 1 (SERPINE1) was further examined using gain- and loss-of-function approaches, followed by immunoblotting, enzyme-linked immunosorbent assay, reactive oxygen species analysis, cell adhesion, Transwell assays, Cell Counting Kit-8, and JC-1 staining. Results Serum transcriptomes showed clear separation between GDM and controls, with 1252 differentially expressed genes identified, including 1095 upregulated and 157 downregulated genes. Integrated analyses converged on immune–coagulation activation, platelet and innate immune signaling, extracellular remodeling, and attenuation of tricarboxylic acid cycle-centered metabolism. Network analysis highlighted vascular, coagulation, and lipid-metabolic hubs, including SERPINE1. In HUVECs, glucolipotoxic stress reproduced an endothelial inflammatory and immune–coagulation-associated expression pattern and markedly induced SERPINE1. Functional experiments showed that SERPINE1 enhanced phosphatidylinositol 3-kinase/protein kinase B signaling, inflammatory and oxidative responses, endothelial activation-related phenotypes, and mitochondrial membrane potential loss. Conclusion GDM serum exhibit coupled immune–coagulation and mitochondrial-metabolic remodeling. SERPINE1 emerges as a functionally relevant endothelial effector linking glucolipotoxic stress to inflammatory activation and mitochondrial dysfunction.