By integrating bioinformatics, experimental validation, and clinical correlation analyses, we identified six SFs (CRNKL1, SNRPB2, RBMX2, DDX46, PPWD1, and CFAP20) that are aberrantly overexpressed in esophageal cancer and tightly linked to poor prognosis. The gene discussed is PPWD1; the disease is esophageal cancer.