Nuclear factor erythroid 2-related factor 2–Kelch-like ECH-associated protein 1 protein–protein interface (Nrf2–KEAP1 interface) (Nrf2–KEAP1 interface)

The Nrf2–KEAP1 protein–protein interface is a master regulatory switch for the cellular antioxidant response. Under basal conditions, Kelch-like ECH-associated protein 1 (KEAP1) acts as a substrate adapter for a Cullin 3-based E3 ubiquitin ligase, binding to Nuclear factor erythroid 2-related factor 2 (Nrf2) and targeting it for proteasomal degradation [UniProt: Q16236, Q14145]. Upon exposure to oxidative stress or electrophiles, specific cysteine residues on KEAP1 are modified, or the interface is sterically hindered, preventing Nrf2 ubiquitination. This allows Nrf2 to accumulate, translocate to the nucleus, and bind to Antioxidant Response Elements (ARE) to drive the expression of cytoprotective genes such as HO-1 and NQO1 [PubMed: 22230511]. Pharmacological modulation of this interface is a key strategy for treating diseases characterized by oxidative stress and inflammation, including multiple sclerosis and Friedreich's ataxia [FDA: Skyclarys, Tecfidera]. However, chronic activation of Nrf2 can also support the survival of cancer cells, presenting a complex therapeutic challenge known as the Nrf2 paradox [Nature Reviews Cancer, PMID: 29449664].

Other names

NFE2L2-KEAP1 interfaceKeap1-Nrf2 pathwayNrf2-Keap1 systemNrf2-Keap1-ARE signaling pathway

Inhibition of the Nrf2–KEAP1 interaction through covalent modification of KEAP1 cysteine sensors (e.g., Cys151) or direct non-covalent blockade of the Kelch domain, preventing Nrf2 ubiquitination and degradation, thereby promoting its nuclear translocation and activation of antioxidant response element (ARE)-driven genes [Nature Reviews Drug Discovery, PMID: 24439317].