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

The Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) complex serves as the primary cellular sensor and master regulator of the antioxidant response. Under basal conditions, Keap1 functions as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and subsequent proteasomal degradation (UniProt Q16236, Q14145). Upon exposure to oxidative stress or electrophilic insults, specific reactive cysteine residues on Keap1 are modified, leading to a conformational change that prevents Nrf2 degradation. This allows Nrf2 to accumulate, translocate to the nucleus, and bind to Antioxidant Response Elements (ARE) in the promoter regions of cytoprotective genes, including those for Heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) (PubMed 25913011). Pharmacological modulation of this pathway, primarily through Nrf2 activators like dimethyl fumarate and omaveloxolone, is utilized to treat multiple sclerosis and Friedreich's ataxia by enhancing cellular resilience against oxidative damage (FDA, 2023). However, chronic Nrf2 activation is a double-edged sword; while it prevents cancer initiation in healthy tissues, it can promote the survival and chemoresistance of established tumor cells, a phenomenon known as the Nrf2 paradox.

Other names

NFE2L2-KEAP1 axisNrf2 pathwayARE signaling pathwayINRF2-NFE2L2 complexNrf2-Keap1-Cul3 complex

Activation of Nrf2 signaling via inhibition of Keap1-mediated degradation, often through covalent modification of Keap1 cysteine residues or disruption of the Nrf2-Keap1 protein-protein interaction.