EphA5 Expression Predicts Better Survival Despite an Association with Proliferative Activity in Endometrial Cancer

Background/Objectives: Eph receptor A5 (EphA5) is a receptor tyrosine kinase that is implicated in multiple malignancies, although its role in endometrial cancer (EC) remains unclear. The aim of this study was to investigate the clinicopathological significance of EphA5 expression in EC and explore its association with proliferative and metabolic markers. Methods: We retrospectively analyzed 75 EC tissue samples from treatment-naïve patients by using immunohistochemistry and H-score quantification. Associations between EphA5 expression and clinicopathological parameters were assessed through logistic regression analysis. Kaplan-Meier analysis was used to evaluate survival outcomes. Correlation analysis, stratified according to cancer stage, was used to explore biomarker interactions. Results: High EphA5 expression levels were significantly associated with elevated Ki-67 expression (adjusted odds ratio (aOR): 1.08 per 1-point H-score increase, p = 0.024) and decreased pAMPK expression (aOR: 0.89 per 1-point H-score increase, p = 0.024), indicating its involvement in proliferative and metabolic pathways. Paradoxically, patients with high EphA5 levels had significantly better overall survival probabilities (H-score > 105, log-rank p = 0.007). Stage-specific analyses suggested that EphA5 levels correlated with proliferation in early-stage disease and epithelial-mesenchymal transition in advanced stages. Conclusions: EphA5 may act as a context-dependent biomarker in EC. Despite its positive correlation with proliferation and negative association with metabolic stress signaling, high EphA5 expression levels were predictive of a favorable prognosis.