Teng Xu and colleagues identified that, in head and neck squamous cell carcinoma (HNSCC), the DLG motif within tumor necrosis factor-α-induced protein 2 (TNFAIP2) competes with the Kelch domain of Keap1, thereby inhibiting the ubiquitin-proteasome-mediated degradation of NRF2. Here, NFE2L2 is linked to head and neck squamous cell carcinoma.