In this study, we aimed to: (1) develop a PDCD4-based gene expression signature using TCGA-KIRC RNA-sequencing data; (2) evaluate its prognostic value for overall survival in a large cohort of ccRCC patients; (3) validate the signature in multiple independent external datasets across different microarray platforms; and (4) employ mediation analysis to determine whether the signature’s prognostic effect operates independently or through its associations with tumor stage and grade. Here, PDCD4 is linked to neoplasm.