Under normal conditions, Nrf2 is bound to Keap1 (Kelch-like ECH-associated protein 1) in the cytoplasm, which targets it for ubiquitination and subsequent degradation. Upon exposure to oxidative stress or electrophilic agents, Nrf2 is released from Keap1, allowing it to translocate into the nucleus. Once in the nucleus, Nrf2 binds to the antioxidant response element (ARE) in the DNA, leading to the transcription of genes involved in detoxification and cytoprotection. Nrf2 activators facilitate the release of Nrf2 from Keap1, either by modifying cysteine residues on Keap1 or by competing for the binding sites, thereby enhancing the expression of protective genes.
