Nuclear factor erythroid 2-related factor 2 (NFE2L2) and Kelch-like ECH-associated protein 1 (KEAP1) (Nrf2 (for Nuclear factor erythroid 2-related factor 2), Keap1 (for Kelch-like ECH-associated protein 1))

The Nrf2–Keap1 pathway is a key cellular defense system against oxidative and electrophilic stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper (bZIP) transcription factor that, under unstressed conditions, is retained in the cytoplasm and targeted for proteasomal degradation by binding to its repressor, Kelch-like ECH-associated protein 1 (Keap1), an adaptor for E3 ubiquitin ligase complexes. Upon exposure to oxidative or electrophilic stress, critical cysteine residues in Keap1 are modified, inhibiting Nrf2 ubiquitination, allowing Nrf2 to translocate into the nucleus, dimerize with Maf proteins, and drive the transcription of cytoprotective genes via antioxidant response elements (AREs). This pathway regulates not only oxidative stress response but also influences inflammation, metabolism, and disease pathogenesis. Malfunction (mutation or deregulation) of this pathway is implicated in cancer, chronic inflammatory conditions, neurodegeneration, and more. Pharmacologic targeting of the Nrf2–Keap1 axis is being explored for a variety of conditions, but there are concerns regarding long-term safety, particularly for cancer risk and therapy resistance if Nrf2 is constitutively activated. The canonical name is best described as two distinct molecules: "Nuclear factor erythroid 2-related factor 2 (NFE2L2)" and "Kelch-like ECH-associated protein 1 (KEAP1)", which together form the regulatory pathway commonly called the Keap1-Nrf2 pathway.

Other names

NFE2L2 (for Nrf2)KEAP1 (for Keap1)NF-E2-related factor 2Nuclear factor (erythroid-derived 2)-like 2Kelch-like ECH-associated protein 1INrf2 (occasionally for Keap1)

Inhibition of Keap1-Nrf2 interaction to enable Nrf2 nuclear translocation and activation of antioxidant response element (ARE)-driven gene expression. Covalent modification of cysteine residues on Keap1, preventing Nrf2 ubiquitination and degradation.