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

The Keap1-Nrf2 pathway is the master regulator of the cellular antioxidant response, primarily involving the interaction between the transcription factor Nrf2 and its negative regulator, the E3 ubiquitin ligase adaptor Keap1 (Yamamoto et al., 2018, Physiol Rev). Under normal conditions, Keap1 targets Nrf2 for proteasomal degradation, maintaining low basal levels of the transcription factor. In response to oxidative stress or electrophilic drugs, Keap1 is modified, leading to Nrf2 stabilization and nuclear translocation. Once in the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to drive the expression of genes involved in detoxification and redox balance. Therapeutic activation of this pathway is utilized in treating multiple sclerosis (Dimethyl fumarate, FDA 2013) and Friedreich's ataxia (Omaveloxolone, FDA 2023) to mitigate oxidative damage. However, chronic activation of Nrf2 in cancer cells can lead to therapeutic resistance and enhanced tumor growth, a phenomenon known as the Nrf2 paradox. Drug development focuses on small molecule activators that disrupt the Keap1-Nrf2 protein-protein interaction or modify Keap1 cysteine sensors. Safety concerns include cardiovascular risks, as seen in the termination of the BEACON trial for bardoxolone methyl due to heart failure events (de Zeeuw et al., 2013, NEJM).

Other names

Nrf2-Keap1 pathwayNFE2L2-KEAP1 axisAntioxidant response element (ARE) pathwayElectrophile response element (EpRE) pathway

Stabilization of Nrf2 through the inhibition of Keap1-mediated ubiquitination, leading to increased transcription of cytoprotective and antioxidant genes via Antioxidant Response Elements (ARE) (Yamamoto et al., 2018, Physiol Rev).