Oxidative stress response regulators

Oxidative stress response regulators are a diverse class of proteins, primarily transcription factors and their associated sensors, that coordinate cellular defenses against reactive oxygen species (ROS) and electrophilic stress. The central component of this system in humans is the Nuclear factor erythroid 2-related factor 2 (Nrf2), which is regulated by its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Under normal conditions, Keap1 targets Nrf2 for proteasomal degradation; however, oxidative or electrophilic stress modifies Keap1, allowing Nrf2 to accumulate and translocate to the nucleus. Once in the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to induce the expression of a battery of cytoprotective genes, including heme oxygenase-1 (HO-1) and glutathione-related enzymes. Dysregulation of these regulators is implicated in a wide range of diseases, including neurodegeneration, chronic inflammation, and cardiovascular disorders. Therapeutic strategies focus on activating this pathway to enhance endogenous antioxidant capacity, with drugs like dimethyl fumarate and omaveloxolone already in clinical use. Nevertheless, the "Nrf2 paradox"—whereby Nrf2 activation can protect cancer cells from oxidative damage and therapy—remains a significant challenge in drug development.

Other names

Antioxidant response regulatorsRedox-sensitive transcription factorsNrf2-Keap1 pathway componentsOxidative stress sensorsPhase II enzyme regulators

Activation of the Nrf2-ARE signaling pathway, inhibition of Keap1-mediated degradation of Nrf2, and induction of phase II antioxidant and detoxification enzymes.