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Esophageal cancer occurs when the uncontrolled growth of abnormal cells in the food tube (oesophagus). Esophageal cancer is one of the most prevalent malignant tumors in the food tract with worldwide distribution due to late clinical development, rapid growth, and very poor survival. Also, the reason for this poor prognosis is that Esophageal cancer normally indicates widespread local tumor invasion and frequent spread to metastatic locations, especially regional lymph nodes. The objective of this study is to analyse all genes involved in protein-protein interaction through a systems biology approach and to identify key genes involved in Esophageal cancer. There is a total of 108 genes that causes Esophageal cancer and a protein-protein network was constructed and analyzed using these genes. The genes are obtained from the UniProt database using STRING and Cytoscape 3.7.1 tools. Moreover, the functional enrichment analysis was done to identify the key genes by using CentiScape and FUNRICH database. RBM8A, ZWINT, EIF4A3, BRCA2, GNB2L1 were recognized as the main genes in the network based on network topology parameters. Among them, the EIF4A3 gene with the greatest betweenness centrality and node degree was acquired as a super hub gene. The assessment of functional enrichment was carried out using the FUNRICH database. Conclusion From this study, the Eukaryotic initiation factor 4A-3 (EIF4A3) identified as one of the key genes in Esophageal cancer. This result suggests the potential role for EIF4A3 to serve as a diagnostic marker or therapeutic target for Esophageal cancer.