NRF2: New Mechanistic Insights and Therapeutic Perspectives

Targeted modulation of a dynamic interplay between transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), is of paramount importance in maintaining redox, metabolic, and protein homeostasis and regulating inflammation responses. Indeed, inducible NRF2 activation promotes cytoprotective mechanisms against many immune, neurodegenerative, and metabolic disorders with oxidative stress and inflammation as underlying pathological features. In this ARS Forum, five state-of-the-art reviews and two original research communications report on canonical and newly discovered molecular mechanisms by which the NRF2-KEAP1 axis controls fundamental cell life or death decisions and exerts biological functions under environmental and endogenous stress conditions. Although the use of NRF2 activators represents a promising pharmacological strategy to regain and maintain homeostasis, challenges regarding their double-edged character, target specificity, pharmacodynamic properties, efficacy, and safety must be critically considered. More translational studies are warranted before NRF2 agonists (inducers or enhancers) become an integral part of our therapeutic armamentarium. Antioxid. Redox Signal. 40, 632-635.