**Background:** NAD(P)H quinone dehydrogenase 1 (NQO1) is a cytoprotective flavoprotein that detoxifies quinones, reduces reactive oxygen species (ROS), and regenerates antioxidants like vitamin E and coenzyme Q10. It is expressed in the central nervous system (CNS), predominantly in astrocytes and oligodendrocytes, with lower levels in neurons. NQO1 is regulated by the Nrf2-KEAP1-ARE signaling pathway and interacts with other pathways such as CREB-Nrf2/HO-1 and PI3K/Akt. Genetic polymorphisms, particularly C609T (P187S), reduce enzyme activity and are associated with increased risk of neurological disorders. This narrative review synthesizes current knowledge on NQO1's modulatory mechanisms and its potential diagnostic, prognostic, and therapeutic roles in various CNS disorders.
**Methods:** The authors conducted a comprehensive narrative review of experimental and clinical studies examining NQO1 in neurological disorders. They summarized findings from in vitro cell culture experiments, in vivo animal models, and human studies (including postmortem tissue analyses, case-control studies, and clinical trials). The review covers Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), cerebrovascular diseases, traumatic brain injury (TBI), epilepsy, amyotrophic lateral sclerosis (ALS), and brain tumors. Key methodologies included molecular biology, histopathology, immunohistochemistry, behavioral assessments, biochemical analysis, electrophysiological recordings, and bioinformatic analysis.
**Key Results:** In AD, NQO1 expression increases in early stages but declines later; the C609T polymorphism is associated with faster Aβ1-42 aggregation. In PD, NQO1 is upregulated in early/intermediate stages but decreases in end-stage; NQO1 activation protects dopaminergic neurons from MPTP-induced toxicity. In MS, NQO1 is upregulated in active and chronic active lesions, and its induction by dimethyl fumarate correlates with better clinical outcomes. In cerebrovascular disease, NQO1 upregulation facilitates ischemic preconditioning and reduces injury after stroke. In TBI, Nrf2 pathway activation upregulates NQO1 and improves neurological outcomes. In epilepsy, NQO1 expression is increased in human epileptic tissue, and NQO1-/- mice exhibit spontaneous seizures. In ALS, NQO1 levels are reduced in motor neurons, and Nrf2 activation improves survival in SOD1-G93A mice. In brain tumors, NQO1 has a dual role: it can promote glioblastoma cell proliferation but also sensitize cells to certain therapies; high NQO1 expression correlates with radiation resistance in diffuse intrinsic pontine glioma.
**Clinical Implications:** NQO1 represents a promising biomarker for oxidative stress and a therapeutic target across multiple CNS disorders. Nrf2 inducers (e.g., dimethyl fumarate, sulforaphane) that upregulate NQO1 have shown neuroprotective effects in MS, stroke, TBI, and epilepsy. NQO1 polymorphisms may predict treatment response (e.g., natalizumab in MS, temozolomide in glioblastoma). However, challenges include off-target effects of NQO1 modulators, the dual role of NQO1 in cancer, and the need for selective compounds. Future research should focus on personalized medicine approaches, nanotechnology-based drug delivery, and integration of multi-omics data to fully exploit NQO1's therapeutic potential.