The Keap1-Nrf2 pathway: From mechanism to medical applications

The Keap1-Nrf2 pathway is the body’s primary inducible response to oxidative stress. Since the discovery in 1997 that Nrf2 is responsible for the expression of cytoprotective genes, an intricate molecular mechanism has been revealed through which the stress sensor protein Keap1 tightly regulates Nrf2 activity. In the nonstressed state, Keap1 promotes the ubiquitin-dependent degradation of Nrf2, while in response to oxidative or electrophilic stress, Keap1‘s ubiquitin ligase activity is inactivated, allowing Nrf2 to escape degradation and activate its antioxidant and anti-inflammatory transcription programs. Recent advances have revealed that in addition to oxidative stress, dysfunctional autophagy, endogenous primary metabolism metabolites, and immune metabolites are also able to regulate Nrf2‘s activity. This integration of Nrf2 activity into multiple cellular pathways highlights its importance for cellular survival and homeostasis and suggests that the pharmacological modulation of Nrf2 activity can provide beneficial effects in a number of diverse disease contexts.