Kelch-like ECH-associated protein 1 (KEAP1)–Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis (KEAP1–Nrf2 axis)

The KEAP1–Nrf2 signaling axis is the principal cellular mechanism for defending against oxidative and electrophilic stress (PMID: 29420481). It consists of the sensor protein Kelch-like ECH-associated protein 1 (KEAP1) and the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) (UniProt: Q14145, Q16236). Under basal conditions, KEAP1 facilitates the ubiquitination and subsequent degradation of Nrf2 via the Cullin 3-E3 ligase complex. When cells encounter stress, KEAP1 is inactivated, allowing Nrf2 to accumulate and translocate to the nucleus where it induces the expression of antioxidant response element (ARE)-containing genes. These genes encode proteins involved in detoxification, glutathione synthesis, and redox balance, such as heme oxygenase-1 (HO-1) and NQO1. Pharmacological activation of this axis is used to treat inflammatory and autoimmune conditions, such as multiple sclerosis and Friedreich's ataxia (FDA: Skyclarys, Tecfidera). However, chronic activation of Nrf2 in cancer cells can lead to "Nrf2 addiction," where the pathway promotes tumor survival and resistance to chemotherapy (PMID: 30721742). Current drug development focuses on both electrophilic activators that modify KEAP1 cysteines and non-electrophilic inhibitors of the KEAP1–Nrf2 protein-protein interaction.

Other names

KEAP1-NFE2L2 pathwayNrf2-KEAP1 pathwayKelch-like ECH-associated protein 1/Nuclear factor erythroid 2-related factor 2 systemAntioxidant Response Element (ARE) pathway

Activation of the Nrf2-mediated antioxidant response by inhibiting the KEAP1-Cullin 3 E3 ubiquitin ligase complex, thereby preventing Nrf2 degradation and promoting its nuclear translocation.