Altered Placental Ezrin Expression in Gestational Diabetes Mellitus: An Immunohistochemical and Bioinformatic Analysis

Background/Objectives: Gestational diabetes mellitus (GDM) is associated with placental structural and functional alterations that may impair trophoblast integrity and maternal–fetal exchange. Ezrin, radixin, and moesin (ERM) proteins are membrane–cytoskeleton linker proteins involved in microvillous organization, cell polarity, and signal transduction. This study aimed to investigate placental ERM protein expression in GDM and to explore ERM-associated molecular pathways through bioinformatic analysis. Methods: This prospective observational study included placental tissues obtained from 40 women with GDM and 40 healthy pregnant women. Immunohistochemical staining for ezrin, radixin, and moesin was performed on paraffin-embedded placental sections, and quantitative image analysis was conducted using QuPath software (version 0.7.0) to calculate H-scores. Correlation and receiver operating characteristic (ROC) analyses were performed to evaluate associations between ERM expression and clinical parameters. In addition, bioinformatic analyses were conducted using the publicly available GSE154414 placental transcriptomic dataset to investigate ERM-associated signaling pathways and interaction networks. Results: Ezrin immunoreactivity was significantly increased in the GDM group compared with controls (118.63 ± 20.56 vs. 107.95 ± 17.41, p = 0.026), whereas Radixin and Moesin expression levels did not differ significantly between groups (p > 0.05). Ezrin expression demonstrated significant positive correlations with maternal body mass index, birth weight, fasting glucose, and HbA1c levels. ROC analysis demonstrated modest discriminatory performance of the Ezrin H-score for distinguishing GDM from control pregnancies (AUC = 0.645, p = 0.018). Bioinformatic analyses identified enrichment of ERM-associated pathways involved in cytoskeletal remodeling, inflammatory signaling, and protein phosphorylation-related cellular processes. Conclusions: Placental Ezrin expression was significantly increased in women with GDM and was positively associated with maternal glycemic parameters. These findings suggest that altered Ezrin expression may reflect adaptive cytoskeletal remodeling in diabetic placentas. ERM-associated signaling pathways may contribute to placental responses to metabolic stress in GDM.