Therefore, we used nicotine and arecoline to further investigate the role of NRF2 in HNSCC, as long-term nicotine (e.g., cigarette smoking) and arecoline (e.g., betel nut chewing) exposure have been reported to promote head and neck carcinogenesis and progression 28, 45, 46. The gene discussed is NFE2L2; the disease is head and neck squamous cell carcinoma.