In conclusion, with sophisticated bioinformatic analysis of transcriptome data from cancer and normal tissues, we have identified a novel panel of DEGs for HPV-related HNSCC, which included ITGA5, PLAU, PLAUR, SERPINE1, and TGFB1. Following verification and validation of the expression levels and clinical impact of these candidate genes in multiple databases, we propose that this panel of candidate genes could potentially be used as a biomarker panel in the prognostic evaluation and early detection of HPV-related HNSCC. This evidence concerns the gene SERPINE1 and head and neck squamous cell carcinoma.