The KEAP1-NRF2 system plays a central role in cytoprotection in defence mechanisms against oxidative stress. The KEAP1-NRF2 system has been regarded as a sulfur-utilizing cytoprotective mechanism, because KEAP1 serves as a biosensor for electrophiles by using its reactive thiols and NRF2 is a transcriptional factor regulating genes involved in sulfur-mediated redox reactions. NRF2 is a key regulator of cytoprotective genes, such as antioxidant and detoxification genes, and also possesses potent anti-inflammatory activity. Recently NRF2 has been the focus of attention as a regulator of cellular metabolism and mitochondrial function. The NRF2-mediated regulatory mechanisms of metabolites and mitochondria have been considered diverse, but have not yet been fully clarified. This review article provides an overview of molecular mechanisms that regulate NRF2 signalling and its cytoprotective roles, and highlights NRF2 contribution to cellular metabolism, particularly in the context of mitochondrial function and newly-found sulfur metabolism. LINKED ARTICLES: This article is part of a themed issue Recent Innovations in Targeting Redox Biology for Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.1/issuetoc.
Keywords: antioxidant; metabolism; mitochondria; supersulfide.
© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.