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

The Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 (KEAP1–NRF2) complex is the primary regulator of the cellular antioxidant and cytoprotective response. Under basal conditions, KEAP1 acts as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase complex, which targets NRF2 for continuous ubiquitination and proteasomal degradation (Yamamoto et al., 2018, Physiol Rev). When the cell encounters oxidative or electrophilic stress, specific cysteine residues on KEAP1 (such as Cys151, Cys273, and Cys288) are modified, causing a conformational change that prevents NRF2 degradation. This allows NRF2 to accumulate, translocate to the nucleus, and bind to Antioxidant Response Elements (ARE) to drive the transcription of genes involved in glutathione synthesis, phase II detoxification, and redox homeostasis (Kansanen et al., 2013, Redox Biol). Pharmacological modulation of this complex is a major therapeutic strategy, with drugs like Dimethyl fumarate and Omaveloxolone approved for treating multiple sclerosis and Friedreich's ataxia, respectively (Lynch et al., 2023, N Engl J Med). However, the pathway is a double-edged sword; while it protects healthy cells, its constitutive activation in many cancers promotes tumor survival and confers resistance to chemotherapy (Rojo de la Vega et al., 2018, Cancer Cell).

Other names

KEAP1-NFE2L2 complexNRF2-KEAP1 complexINRPWKelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2 pathway

Activation of the NRF2 pathway by inhibiting the KEAP1-mediated degradation of NRF2, typically through covalent modification of KEAP1 cysteine residues or non-covalent inhibition of the KEAP1-NRF2 protein-protein interaction, leading to NRF2 nuclear translocation and induction of antioxidant response element (ARE)-driven genes.