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

The Nuclear factor erythroid 2-related factor 2–Kelch-like ECH-associated protein 1 (Nrf2–Keap1) pathway is a central cellular mechanism for protection against oxidative and electrophilic stress[1][7][8]. Nrf2 is a transcription factor that, under homeostatic conditions, is sequestered in the cytoplasm by Keap1, a BTB-Kelch family protein serving as an adaptor for an E3 ubiquitin ligase complex, which targets Nrf2 for proteasomal degradation[3][7][8]. Upon exposure to oxidative or electrophilic stress, key cysteine residues on Keap1 are modified, leading to conformational change and inhibition of the Keap1-mediated ubiquitination, allowing Nrf2 to accumulate, translocate to the nucleus, and bind antioxidant response elements (ARE) in the promoters of target genes[1][7]. This results in upregulation of a wide range of cytoprotective, antioxidant, and detoxifying genes. Dysregulation of this pathway, through mutations in KEAP1 or NRF2 or persistent activation, is implicated in cancer development, chemoresistance, chronic inflammation, and several other diseases[3][4][5][8]. Pharmacological modulation, both activation and inhibition, of the Nrf2–Keap1 pathway is an area of active therapeutic research, with approved drugs such as dimethyl fumarate for multiple sclerosis, and investigational agents like bardoxolone methyl being evaluated in various conditions. While the pathway is protective in normal tissue, chronic or constitutive pathway activation can contribute to cancer progression and resistance to therapy[5][8]. Key genes regulated by Nrf2 include NQO1, HO-1, glutathione S-transferases, and other phase II detoxifying and antioxidant enzymes. The pathway is considered a validated drug target, but there are important challenges regarding the context-specific effects and safety of long-term modulation[1][4][7][8].

Other names

Nrf2 pathwayKeap1-Nrf2 pathwayKeap1–Nrf2–ARE pathwayNuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 axisKeap1-Nrf2 signaling pathway

Nrf2 induction (activators increase Nrf2 activity by disrupting Keap1-mediated degradation, enhancing antioxidant gene expression); Nrf2 inhibition (inhibitors block Nrf2 activity, potentially sensitizing cancer cells to chemotherapy); Direct disruption of Keap1-Nrf2 interaction (prevents Nrf2 ubiquitination and degradation); Indirect modulation via upstream signaling (e.g., PI3K/AKT pathway)