Transcription regulation results showed that eigth high‐risk lipid metabolism‐related genes (GLA, ACAT1, DGKG, TXNRD1, PTDSS1, SMS, PIP5K1B, and CAV1) and eight TFs (PPAPG, MYH11, H2AFX, HEY1, CBX2, SNAI2, SPDEF, and FOXA2) were strongly associated with poor HNSCC prognosis. This evidence concerns the gene PTDSS1 and head and neck squamous cell carcinoma.