However, numerous studies have revealed that components of the antioxidant defense system, such as paraoxonase-2 (PON2) and the Nuclear Factor Erythroid 2-Related Factor 2/Kelch Like ECH Associated Protein 1 (NRF2/KEAP1) signaling axis, can paradoxically support tumor progression and therapy resistance in HNSCC. This evidence concerns the gene NFE2L2 and head and neck squamous cell carcinoma.