Kelch-like ECH-associated protein 1 (KEAP1) (KEAP1)

Kelch-like ECH-associated protein 1 (KEAP1) is a primary regulator of the cellular antioxidant response, functioning as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase complex (Source: UniProt Q14145). Under basal conditions, KEAP1 binds to the transcription factor NRF2 via its C-terminal Kelch domain, specifically interacting with the ETGE and DLG motifs in the NRF2 Neh2 domain to facilitate its ubiquitination and proteasomal degradation (Source: PMC4488171). Upon exposure to oxidative stress or electrophilic insults, the KEAP1-NRF2 interaction is disrupted—either through modification of KEAP1 cysteine residues or direct competitive inhibition at the Kelch domain interface—allowing NRF2 to translocate to the nucleus (Source: PMID: 36086898). In the nucleus, NRF2 binds to antioxidant response elements (AREs) to induce the expression of cytoprotective and detoxification genes such as NQO1 and HMOX1 (Source: PMID: 26238464). While NRF2 activation is therapeutic in chronic inflammatory and neurodegenerative diseases, its constitutive activation in certain cancers can promote tumor survival and resistance to therapy, a phenomenon known as the "NRF2 paradox" (Source: PMC4488171). Modern drug discovery efforts focus on developing non-covalent protein-protein interaction (PPI) inhibitors that target the Kelch domain to achieve more selective NRF2 activation compared to traditional electrophilic compounds (Source: PMID: 36086898).

Other names

KEAP1Kelch-like ECH-associated protein 1INRPWKIAA0132KLHL19Kelch-like protein 19

Direct inhibition of the KEAP1-NRF2 protein-protein interaction (PPI) at the Kelch domain interface, preventing NRF2 ubiquitination and promoting its nuclear translocation and activation of antioxidant response element (ARE)-driven genes.