Nuclear factor erythroid 2-related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) complex (Nrf2–Keap1 complex)

The Nuclear factor erythroid 2-related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) complex is a master regulator of the cellular antioxidant response (UniProt: Q16236, Q14145). Under basal conditions, Keap1 acts as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase, targeting Nrf2 for rapid proteasomal degradation (PubMed: 14585973). Upon exposure to oxidative stress or electrophilic compounds, specific cysteine residues on Keap1, such as C151, are modified, leading to a conformational change that prevents Nrf2 ubiquitination (PubMed: 15983046). This allows Nrf2 to translocate to the nucleus, where it binds to Antioxidant Response Elements (ARE) to induce the transcription of cytoprotective genes involved in detoxification and redox balance (PubMed: 25911330). Pharmacological modulation of this complex, primarily through Nrf2 activators like dimethyl fumarate and omaveloxolone, is a major therapeutic strategy for treating chronic inflammatory and neurodegenerative diseases (FDA: Tecfidera, Skyclarys). However, constitutive activation of Nrf2 is also associated with cancer progression and drug resistance, presenting a complex therapeutic window often referred to as the "dark side" of Nrf2 (PubMed: 23434377).

Other names

NFE2L2–KEAP1 complexNrf2–Keap1 pathwayNrf2–Keap1–Cul3 complexNrf2–Keap1–Cullin-3 E3 ubiquitin ligase complex

Activation of Nrf2 by inhibiting its Keap1-mediated ubiquitination and degradation, either through covalent modification of Keap1 cysteine residues or direct disruption of the Nrf2–Keap1 protein-protein interaction (PubMed: 15983046, 25911330).