Overall, our data support the following conclusions: first, RAP80 is a novel and independent biomarker for predicting the development of ESCC; second, targeting RAP80 is a promising way for ESCC patients’ therapy; third, combination application of RAP80 inhibitors and ATM inhibitors or USP13 inhibitors will remarkably increase the therapeutic opportunities for ESCC patients in the future. The gene discussed is USP13; the disease is esophageal squamous cell carcinoma.