Activation of transcription factor Nrf2 as a strategy to restore the cellular redox and protein homeostasis

Disrupted redox and protein homeostasis and chronic inflammation are characteristic features of most human pathologies. The transcription factor Nrf2 regulates the expression of large networks of genes encoding proteins that provide powerful and long-lasting protection against damage by oxidants and pro-inflammatory agents. Most pharmacological activators of Nrf2 (termed inducers) are electrophiles that target discreet highly reactive sensor cysteines within Kelch-like ECH-associated protein 1 (Keap1), the main negative regulator of Nrf2, impairing the repressor function of Keap1, and allowing for Nrf2 accumulation and enhanced transcription of its target genes. The Nrf2 regulatory network includes drug metabolizing, antioxidant, anti-inflammatory and metabolic enzymes, proteasomal subunits and autophagy-related proteins, and thus has a critical role in the maintenance of the cellular redox and protein homeostasis, and in the resolution of inflammation. Pharmacological Nrf2 activation with electrophilic inducers, some of which are in clinical trials, shows multiple beneficial effects in cell culture and animal models of epilepsy, Parkinson’s disease, and Huntington’s disease.