Integrated Transcriptomics and Experimental Validation Reveal That Ellagic Acid Alleviates Fuchs Endothelial Corneal Dystrophy via PLAU/NF-κB Signaling

Purpose: The purpose of this study was to investigate the role of ellagic acid (EA) in alleviating oxidative stress and inflammation in Fuchs endothelial corneal dystrophy (FECD) and to evaluate its therapeutic potential by targeting urokinase-type plasminogen activator (PLAU) and modulating NF-κB signaling. Methods: We integrated bioinformatics analyses using multiple databases to identify EA target genes and FECD-related differentially expressed genes (DEGs), along with functional enrichment. Experimental validation was carried out in H2O2-stimulated and UVA-irradiated human corneal endothelial cell (CEC) line B4G12. Molecular docking, receiver operating characteristic (ROC) analysis, immune infiltration, and siRNA-mediated knockdown were applied to confirm key targets and pathways. Results: Our study identified 1284 EA target genes and 297 FECD-related DEGs, with 21 overlapping genes. From this intersection, a protein-protein interaction (PPI) network identified 10 hub genes. Functional enrichment analysis revealed that these hub genes were significantly associated with key pathways, including NF-κB signaling, inflammatory regulation, and oxidative stress responses. Among these hub genes, PLAU was selected for further investigation due to its key role in the PPI network, its strong correlation with immune cell infiltration, and its high diagnostic value (area under the curve [AUC] = 0.933). Molecular docking predicted a strong interaction between EA and PLAU. Subsequent in vitro experiments demonstrated that EA treatment attenuates inflammation and oxidative damage by targeting PLAU and modulating the NF-κB signaling in CECs. Conclusions: These findings demonstrate that EA alleviates oxidative stress and inflammation in FECD by targeting PLAU and regulating NF-κB signaling. This study supports the therapeutic potential of EA and PLAU as a novel intervention for corneal endothelial diseases.