Nrf2 Activators

NRF2 activators belong to a diverse chemical class characterized by their ability to stimulate the activity of the Nuclear factor erythroid 2-related factor 2 (NRF2) pathway within cells. This pathway plays a crucial role in cellular defense against oxidative stress and maintains redox homeostasis. NRF2 is a transcription factor that regulates the expression of a wide array of genes involved in antioxidant defense, detoxification, and cytoprotective responses. The chemical compounds classified as NRF2 activators are renowned for their ability to modulate NRF2 activity, which, in turn, leads to the upregulation of these protective genes. These compounds typically function by disrupting the interaction between NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (Keap1). Keap1 acts as a molecular sensor for oxidative stress and promotes the degradation of NRF2 under normal conditions. NRF2 activators can either directly modify specific cysteine residues on Keap1, preventing its degradation of NRF2, or indirectly interfere with this interaction, leading to NRF2 stabilization and translocation into the cell nucleus. Once in the nucleus, NRF2 forms a complex with other proteins and binds to antioxidant response elements (AREs) in the DNA, initiating the transcription of genes encoding various antioxidants, phase II detoxifying enzymes, and other cytoprotective proteins. This orchestrated response equips cells with enhanced defense mechanisms against harmful oxidative agents and electrophilic compounds. NRF2 activators encompass a wide range of naturally occurring and synthetic chemicals, including polyphenols, flavonoids, isothiocyanates, and terpenoids, each with its unique molecular mechanisms for activating NRF2 and contributing to cellular resilience against oxidative stress.