In the cell nucleus, NRF2 binds to MAF proteins and antioxidant-responsive elements (AREs) and transactivates downstream targeted genes to promote tumor progression in HNC.202–204 Hence, NRF2 upregulation is positively related to the malignant characteristics of HNC.205 Moreover, NRF2 has been demonstrated to activate the p53/p21 signaling pathway and influence the cell cycle, whereas p62 can inhibit the NRF2/KEAP1/CUL3 complex.206,207 Mutations in the NRF2 pathway are commonly observed in HPV-negative HNC patients, while they are rare in patients with HPV infection208 (Fig. 4). Here, NFE2L2 is linked to neoplasm.