Nrf2 Pathway Involvement in the Central Nervous System

The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a fundamental role in cellular defense against oxidative and electrophilic stress. Within the central nervous system (CNS), where neurons and glial cells are highly susceptible to oxidative damage, Nrf2 has emerged as a master regulator of antioxidant and detoxification responses. Activation of Nrf2 upregulates a wide array of genes involved in maintaining redox balance, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and enzymes responsible for glutathione synthesis. These adaptive responses help protect neurons from oxidative injury and support overall brain homeostasis. Dysregulation of Nrf2 signaling is increasingly recognized as a critical factor in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in acute neurological injuries like ischemic stroke and traumatic brain injury. Pharmacological strategies to activate Nrf2, including synthetic compounds such as dimethyl fumarate and natural agents like sulforaphane, have shown promising neuroprotective effects in both experimental and clinical settings. This review provides a comprehensive discussion on the structure and regulation of the Nrf2 pathway, its physiological role in the CNS, its involvement in neurological diseases, and therapeutic approaches targeting Nrf2 signaling.