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

The Nuclear factor erythroid 2-related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway is the primary cellular defense mechanism against oxidative and electrophilic stress (PubMed: 28238561). Under basal conditions, Keap1 acts as a sensor and an adapter for the Cullin 3-based E3 ubiquitin ligase, constantly targeting Nrf2 for proteasomal degradation (UniProt: Q16236). Upon exposure to oxidative stress or electrophilic compounds, critical cysteine residues on Keap1 are modified, leading to a conformational change that prevents Nrf2 degradation. This allows Nrf2 to translocate into the nucleus, where it binds to the Antioxidant Response Element (ARE) in the promoter regions of over 200 genes involved in detoxification, antioxidant defense, and metabolism (PubMed: 29118384). Pharmacological activation of this pathway is a major therapeutic strategy for treating chronic inflammatory and degenerative diseases, such as multiple sclerosis and Friedreich's ataxia (FDA: Skyclarys, Tecfidera). However, the pathway's role is complex, as constitutive Nrf2 activation in cancer cells can provide a survival advantage and confer resistance to chemotherapy, a phenomenon known as the Nrf2 paradox (PubMed: 29118384). Therapeutic development focuses on balancing cytoprotection with the risk of promoting malignancy, while monitoring biomarkers like NQO1 to assess pathway activation (PubMed: 28238561).

Other names

NFE2L2-KEAP1 pathwayAntioxidant Response Element (ARE) pathwayNrf2 signaling pathway

Drugs targeting this pathway typically function as Nrf2 activators by inhibiting the Keap1-mediated ubiquitination and subsequent proteasomal degradation of Nrf2. This is frequently achieved through the covalent modification of reactive cysteine residues on Keap1, such as Cys151, which induces a conformational change that prevents the Keap1-Cul3-E3 ligase complex from processing Nrf2, allowing the transcription factor to accumulate and translocate to the nucleus (PubMed: 29118384, UniProt: Q14145).