Objective To study the role and gene-related pathways of N6-methyladenosine (m6A) modification in middle and advanced head and neck squamous cell carcinoma (HNSCC), and to propose new perspectives and research references for individualized and precise treatment of HNSCC patients.Methods Cancer and paracancerous tissues (6 samples) from 3 middle and advanced HNSCC patients were selected for sequencing, and the transcriptomes and m6A-related differential genes from the cancer and paracancerous tissues were screened to identify common differential genes shared by both, and the hub genes were identified through gene ontology (GO) analysis, pathway analysis, and protein-protein interaction (PPI) analysis, and then the network of the genes in the network were subsequently subjected to gene set variation analysis (GSVA) to obtain the genes and pathways affected by m6A modification.Results From the differential genes of cancer and paracancer tissues, 96 m6A-related up-regulated genes and 159 m6A-related down-regulated genes were screened out from the transcriptome. Signaling pathway analysis revealed that peroxisome proliferator-activated receptor (PPAR) pathway, immune-related pathway were down-regulated, and metabolic pathway was up-regulated. After constructing the PPI, the cell-cycle protein-dependent kinase 1 (CDK1) was up-regulated, and the decorin (DCN) and anterior gradient 2 (ARG2) were down-regulated. Gene set variation analysis (GSVA) revealed that the PI3K/AKT signaling pathway was up-regulated in cancer tissues. Coexpression analysis of hub genes in the PPIs revealed that AGR2 and CDK1 were very closely linked to iron death-related genes under the regulation of m6A.Conclusions m6A modification is closely associated with iron death-related genes such as FOXA1, ribosomal protein L8(RPL8), DNC, CDK1, apolipoprotein E(ApoE), Periostin (POSTN), YWHAZ, Matrix metalloproteinase-13(MMP13), etc. m6A modification may affect immune and metabolism-related pathways through iron death-related genes, and thus play an important role in middle and advanced HNSCC.