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

The Nrf2–Keap1 regulatory complex is a central cellular redox sensor and effector module critical to the maintenance of antioxidant defenses. Under homeostatic conditions, Keap1 acts as a substrate adaptor for the Cullin 3-based E3 ubiquitin ligase complex, binding Nrf2 at two conserved motifs (ETGE and DLG) and targeting it for proteasomal degradation. In response to oxidative or electrophilic stress, Keap1’s reactive cysteine residues are modified, disrupting Nrf2 ubiquitination and allowing Nrf2 accumulation, nuclear translocation, and induction of cytoprotective genes through ARE promoter elements. The pathway is a validated therapeutic target for a range of diseases where oxidative damage, inflammation, or detoxification capacity is dysregulated, with both Keap1 inhibitors and Nrf2 activators in various stages of drug development. Nrf2–Keap1 function is highly context-dependent: while transient activation is cytoprotective and anti-inflammatory, chronic or constitutive activation can favor cancer cell survival and chemoresistance.

Other names

Nrf2–Keap1 pathwayKeap1–Nrf2 complexNF-E2-related factor 2 – Kelch-like ECH-associated protein 1

Small molecules and drugs can inhibit the Keap1–Nrf2 interaction by covalently modifying critical cysteine residues on Keap1, causing conformational changes that prevent Nrf2 ubiquitination and degradation, thereby stabilizing and activating Nrf2. Stabilized Nrf2 translocates to the nucleus where it induces transcription of cytoprotective genes via ARE binding. Inhibition of Keap1–Nrf2 association prevents Nrf2 proteasomal degradation, increasing the cellular antioxidant response. Some drugs directly bind to Keap1, blocking the Nrf2 degradation site.