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Kelch-like ECH-associated protein 1 (KEAP1) normally promotes Nrf2 ubiquitination and degradation in the cytoplasm under homeostatic conditions. KEAP1 forms a Cullin3-based E3 ligase complex that binds Nrf2's Neh2 domain and ubiquitinates its lysines, targeting it for proteasomal degradation (Nrf2 half-life <20 min) (left).
Under oxidative stress (e.g., ROS), KEAP1 cysteine modifications impair this process, stabilizing Nrf2 for [nuclear translocation](brain://-euOBDZemEqh7vyTX8…