Based on genetic data from our group and others4,7, we sought to pharmacologically deactivate Keap1 in HNSCC cells and found that Keap1 inhibition (i) enhances HNSCC cell radiosensitivity, (ii) elevates the activity of NHEJ-related DNA repair in a Nrf2-dependent manner, (iii) impairs DSB repair through delayed phosphorylation of DNA-PKcs, and (iv) elicits autophagy and increased p62 levels when combined with X-ray irradiation. The gene discussed is KEAP1; the disease is head and neck squamous cell carcinoma.