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

The Kelch-like ECH-associated protein 1 (Keap1) – Nuclear factor erythroid 2-related factor 2 (Nrf2) regulatory complex is the primary cellular sensor for oxidative and electrophilic stress (PMID: 25913011). Under basal conditions, Keap1 acts as a substrate adapter for a Cullin 3-based E3 ubiquitin ligase, which targets Nrf2 for constant proteasomal degradation (UniProt Q14145, Q16236). Upon exposure to oxidative stress or electrophiles, specific cysteine residues on Keap1 are modified, leading to a conformational change that prevents Nrf2 ubiquitination. Consequently, Nrf2 accumulates and translocates to the nucleus, where it binds to Antioxidant Response Elements (ARE) to induce the transcription of cytoprotective genes involved in antioxidant defense, such as HMOX1 and NQO1 (PubMed: 30739908). Pharmacological modulation of this complex, primarily through Keap1 inhibitors or Nrf2 activators like dimethyl fumarate and omaveloxolone, is a major therapeutic strategy for treating chronic inflammatory and neurodegenerative diseases (FDA). However, while Nrf2 activation protects healthy cells, its constitutive activation in cancer cells can promote tumor survival and resistance to therapy, a phenomenon often referred to as the "dark side" of Nrf2 (PubMed: 23435224).

Other names

Keap1-Nrf2 pathwayINRF2-NRF2 complexKelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2 systemNrf2-Keap1-ARE signaling

Activation of the Nrf2-mediated antioxidant response by inhibiting Keap1-mediated degradation of Nrf2. This is typically achieved through covalent modification of Keap1 cysteine residues (e.g., Cys151) by electrophilic molecules or through non-covalent inhibition of the Keap1-Nrf2 protein-protein interaction at the Kelch domain, allowing Nrf2 to accumulate and initiate cytoprotective gene transcription (PMID: 32103301).