In the current study, based on the clinical resource of early ESCC and HGIN, we were able to initially screen specific autoantibody biomarkers for the detection of early ESCC via SERPA combined with nano-LC-Q-TOF-MS/MS, and two potential autoantigens including CETN2 and POFUT1 were frequently recognized by the serum of early ESCC patients. This evidence concerns the gene CETN2 and esophageal squamous cell carcinoma.