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

The Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) regulatory system is the primary cellular defense mechanism against oxidative and electrophilic stress. Under basal conditions, Keap1 acts as a substrate adaptor for the Cullin 3-based E3 ubiquitin ligase complex, targeting Nrf2 for constant proteasomal degradation (Yamamoto et al., 2018, Physiological Reviews). Upon exposure to oxidative stress or electrophiles, specific cysteine residues on Keap1 are modified, leading to a conformational change that prevents Nrf2 ubiquitination. This allows Nrf2 to translocate to the nucleus, where it binds to Antioxidant Response Elements (ARE) in the promoter regions of over 200 genes involved in detoxification, antioxidant defense, and metabolic regulation (Bellezza et al., 2018, Frontiers in Pharmacology). Pharmacological activation of this pathway is a proven therapeutic strategy for inflammatory and neurodegenerative diseases, as evidenced by the clinical use of dimethyl fumarate for multiple sclerosis and omaveloxolone for Friedreich's ataxia (Hecker et al., 2023, Drugs). However, the system's role is complex, as constitutive Nrf2 activation in established tumors can promote cancer cell survival and resistance to chemotherapy, a phenomenon known as the 'dark side' of Nrf2 (Rojo de la Vega et al., 2018, Nature Reviews Cancer).

Other names

KEAP1-NFE2L2 systemNrf2-ARE pathwayINRF2-NFE2L2 complexKeap1-Nrf2-ARE axis

Activation of Nrf2-mediated transcription by inhibiting Keap1-mediated degradation, typically through covalent modification of Keap1 cysteine residues or protein-protein interaction inhibition.