In conclusion, we performed a comprehensive bioinformatics study of HNSCC and constructed 12 ion channel gene signatures (ANO1, AQP1, AQP5, AQP9, BEST2, CHRNA5, KCNJ15, KCNG1, SCNN1G, SCN4A, TRPC1, and VDAC1). Here, BEST2 is linked to head and neck squamous cell carcinoma.