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

The Keap1–Nrf2 signaling pathway is the principal cellular defense mechanism against oxidative and electrophilic stress. Under basal conditions, Keap1 (Kelch-like ECH-associated protein 1) binds to Nrf2 (nuclear factor erythroid 2-related factor 2), retaining it in the cytoplasm and promoting its degradation by the ubiquitin–proteasome system. Upon exposure to oxidative signals or specific small molecules, conformational changes in Keap1 lead to the release of Nrf2, allowing its translocation to the nucleus. Nrf2 then induces the transcription of genes that contain antioxidant response elements (AREs), orchestrating a cytoprotective program. While activation of this pathway protects normal tissues, its persistent activation in cancer cells promotes chemoresistance and tumor progression, making its modulation a double-edged sword in therapeutic strategies[1][2][3][4][5].

Other names

Keap1–Nrf2 pathwayKeap1/Nrf2/ARE pathway (where ARE stands for Antioxidant Response Element)Keap1–Nrf2 axisNrf2 pathwayKelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathway

Activation of Nrf2 (prevents Keap1-mediated ubiquitination, resulting in nuclear translocation and increased expression of cytoprotective genes); Disruption of Keap1–Nrf2 interaction (either by modifying Keap1 cysteines, competing proteins like p62, or through posttranslational modifications); Inhibition of Nrf2 (reducing its transcriptional activity—mainly a strategy in cancer); Modulation of the ubiquitin-proteasome system (Keap1 promotes Nrf2 degradation unless inhibited)