Ninety-six genes showed salient centrality within the PIM mediating the tumorigenesis of OTSCC and BSCC, in which EIF2S1, CAV1, RAN, ANXA5, CYCS, CFL1, MYC, HSP90AA1, PKM, and HSPA5 were significantly linked to a poor prognosis in HNSCC. Here, CFL1 is linked to head and neck squamous cell carcinoma.