Using analysis of oral SCC patient tumors, together with the proteomic and genomic analysis of the HNSCC patient data we reveal an important association of CD109 expression with the expression of IL6Rα, phosphoSTAT3, NRF2 and NRF2 target genes, demonstrating the clinical relevance of the CD109/IL6Rα/STAT3/NRF2/antioxidant pathway as an important molecular mechanism mediating SCC progression. Here, NFE2L2 is linked to head and neck squamous cell carcinoma.