Kelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2 complex (KEAP1-NRF2)

The KEAP1-NRF2 complex is the primary cellular mechanism for sensing and responding to oxidative and electrophilic stress. Kelch-like ECH-associated protein 1 (KEAP1) functions as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase, which targets Nuclear factor erythroid 2-related factor 2 (NRF2) for proteasomal degradation under basal conditions (UniProt Q14145, Q16236). When cells encounter oxidative stress, reactive oxygen species (ROS) or electrophiles modify specific cysteine residues on KEAP1, disrupting the ubiquitination process. This allows NRF2 to accumulate, translocate to the nucleus, and bind to Antioxidant Response Elements (ARE) in the promoters of over 200 cytoprotective genes, including those for glutathione synthesis and detoxification enzymes (PubMed: 25911081). Pharmacological targeting of this complex aims to activate NRF2 to treat chronic inflammatory and degenerative diseases, such as chronic kidney disease and multiple sclerosis (PubMed: 30736422). However, the pathway is a double-edged sword; while it protects healthy cells, many cancers hijack NRF2 activation to survive oxidative stress and resist chemotherapy, making NRF2 inhibition a potential strategy in oncology (PubMed: 23435367).

Other names

KEAP1-NFE2L2 complexINRF2-NRF2 complexKEAP1-NRF2 signaling pathway

Inhibition of KEAP1-mediated ubiquitination of NRF2, leading to NRF2 stabilization, nuclear translocation, and activation of the antioxidant response element (ARE) gene battery.