On the whole, our findings demonstrate that hub genes, CDK1, VEGFA, PRDM10, RUNX1, CDK6, HSP90AA1, MYC, EGR1, and SOX2 regulates ESCC cells via multiple networks involved in various signaling contexts, which would provide novel therapeutic strategies for ESCC patients. Here, EGR1 is linked to esophageal squamous cell carcinoma.