In HNSCC, activation of NRF2 occurs through gain-of-function mutations in NFE2L2 (gene encoding NRF2) 57-59, loss-of-function mutations in the KEAP1 gene 57, disruption of the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex 31, modulation by IL-6 18 or GRP78/PERK signaling 19, and increased protein stability of NRF2 via O-GlcNAcylation 23. This evidence concerns the gene NFE2L2 and head and neck squamous cell carcinoma.