Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain. The transcription factor NRF2 and its repressor KEAP1 have been implicated in the development and progression of chronic diseases. Here, Dinkova-Kostova and colleagues provide an overview of the physiological and pathological roles of NRF2, present emerging pharmacological modulators of the NRF2–KEAP1 axis and highlight associated drug development challenges.