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

The Nrf2–Keap1 complex is a central regulator of the cellular antioxidant and cytoprotective response. Nrf2 (Nuclear factor erythroid 2-related factor 2) is a redox-sensitive transcription factor that controls the expression of genes involved in detoxification and defense against oxidative stress. Under normal conditions, Nrf2 is sequestered in the cytoplasm by Keap1 (Kelch-like ECH-associated protein 1), which acts as a substrate adaptor for the cullin-3 (Cul3) E3 ubiquitin ligase complex, targeting Nrf2 for ubiquitination and proteasomal degradation. Upon oxidative or electrophilic stress, cysteine modifications within Keap1 disrupt its interaction with Nrf2, allowing newly synthesized Nrf2 to accumulate and translocate into the nucleus, where it activates antioxidant response element (ARE)-driven gene expression. This pathway is essential for redox homeostasis and cellular protection, but its dysregulation is implicated in cancer, inflammation, and other diseases. Therapeutic targeting of the Nrf2–Keap1 complex is the focus of research for disease prevention and treatment, with both activators (to enhance protection in degenerative disease) and inhibitors (to mitigate cancer progression or chemoresistance) being explored[1][2][3][4][5][6].

Other names

Nrf2–Keap1 signaling complexNfe2l2–Keap1 complex (Nfe2l2 is the gene encoding Nrf2)Nrf2/Kelch-like ECH-associated protein 1 complex

Inhibition of Nrf2–Keap1 protein–protein interaction (preventing Keap1-mediated degradation of Nrf2); Covalent modification of Keap1 cysteine residues to disrupt Nrf2 binding; Activation/stabilization of Nrf2, leading to increased transcription of antioxidant and cytoprotective genes[1][4][5]