Correlation of high PRDX4 expression with poor prognosis in patients with ESCA: Bioinformatics and in vitro validation

Esophageal cancer (ESCA) is a highly lethal gastrointestinal malignancy with limited therapeutic options. The peroxiredoxin 4 (PRDX4) protein has antioxidant functions and is implicated in various types of cancer, but its role in ESCA remains poorly understood. The purpose of the present study was to investigate PRDX4 expression in ESCA, evaluate its clinical prognostic value, and explore associations with the tumor immune microenvironment and metabolic pathways, with validation by immunohistochemistry (IHC). PRDX4 expression in ESCA was analyzed using UALCAN, SANGERBOX, TIMER, STRING and Kaplan‑Meier Plotter databases. IHC was performed on 60 ESCA and matched normal tissues. Associations with overall survival (OS), progression‑free interval (PFI), disease‑specific survival (DSS), disease‑free interval (DFI), TNM stage and immune cell infiltration were examined. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted. PRDX4 was significantly upregulated in ESCA tissues (P<0.05). IHC showed strong positive staining in all 60 tumor tissues vs. 11/60 normal tissues (P<0.05). High PRDX4 expression correlated with poorer OS [Hazard ratio (HR)=1.82; 95% confidence interval (CI): 1.21‑2.74; P=0.004], PFI (HR=1.65; 95% CI: 1.08‑2.52; P=0.019) and DSS (HR=2.01; 95% CI: 1.32‑3.06; P<0.001), but not with DFI (P=0.35). PRDX4 levels differed significantly across N stages (P=0.006), but not T or M stages. Furthermore, PRDX4 expression was significantly associated with tumor differentiation (P=0.028) and showed a trend towards larger tumor size (P=0.061). PRDX4 expression correlated with infiltration of dendritic cells, macrophages, CD8+ T cells, regulatory T cells, M1 macrophages and activated mast cells. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathways included mitochondrial function, carbon metabolism, tricarboxylic acid cycle and pyruvate metabolism. Protein interaction analysis showed associations with GPX3 and TXN. PRDX4 represents a potential prognostic biomarker for ESCA, with additional diagnostic value suggested by Receiver Operating Characteristic analysis (Area Under Curve=0.969). In conclusion, PRDX4 is significantly overexpressed in ESCA and is associated with poor prognosis, lymph node metastasis, immune infiltration and metabolic reprogramming. The present findings suggest that PRDX4 may serve as a promising prognostic biomarker and a potential therapeutic target for ESCA.