Kelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2-Antioxidant response element signaling pathway (Keap1-Nrf2-ARE pathway)

The Keap1-Nrf2-ARE signaling pathway is the primary mammalian mechanism for cytoprotection against oxidative and electrophilic stress. Under basal conditions, Kelch-like ECH-associated protein 1 (Keap1) acts as a sensor and substrate adaptor for a Cullin 3-based E3 ubiquitin ligase, targeting Nuclear factor erythroid 2-related factor 2 (Nrf2) for rapid proteasomal degradation. Upon exposure to stressors or electrophilic drugs, critical cysteine residues on Keap1 are modified, leading to the stabilization and nuclear translocation of Nrf2. Once in the nucleus, Nrf2 heterodimerizes with small Maf proteins and binds to the Antioxidant Response Element (ARE) in the promoter regions of over 200 genes involved in antioxidant defense, detoxification, and metabolic regulation. While pharmacological activation of this pathway is therapeutic in inflammatory and degenerative diseases—exemplified by the approval of Dimethyl fumarate for multiple sclerosis and Omaveloxolone for Friedreich's ataxia—its constitutive activation in certain cancers can promote tumor cell survival and resistance to therapy.

Other names

Nrf2-Keap1 pathwayNrf2 signaling pathwayAntioxidant response element (ARE) pathwayKeap1-Nrf2 system

Activation of Nrf2 by inhibiting its Keap1-mediated ubiquitination and degradation, leading to nuclear translocation and induction of antioxidant response element (ARE)-driven cytoprotective genes.