Region-Specific NRF2 Signaling in HIV-Associated Neurocognitive Disorders: A Transcriptomic and Computational Histology Study

Background/Objectives. Oxidative stress is a key contributor to HIV-associated neurocognitive disorders (HANDs), yet the regional organization and functional engagement of the NRF2 antioxidant pathway in the human brain remain incompletely defined. This study aimed to characterize NRF2 pathway architecture, baseline brain expression, and disease-associated transcriptional and coexpression remodeling across HAND stages. Methods. The NRF2 signaling network was reconstructed using curated pathway data and protein–protein interaction analysis to identify central hub genes. Baseline expression in the normal human cortex was assessed using the Human Protein Atlas. Transcriptomic profiling of postmortem brain samples from individuals with HAND (GSE35864) was performed using differential expression, hierarchical clustering, and region-specific coexpression analyses across white matter, frontal cortex, and basal ganglia. Results. Low-to-medium baseline expression of NRF2-related genes was observed in the normal cortex. Bulk differential expression revealed minimal NRF2 pathway modulation in the frontal cortex and basal ganglia. On the other hand, white matter exhibited robust NRF2 transcriptional activation specifically in HIV encephalitis (HIVE). Coexpression analysis performed specifically within HAND samples revealed a highly coordinated transcriptional organization of the NRF2 signaling network across all analyzed brain regions. Conclusions. NRF2 signaling in HAND is preserved as a coordinated transcriptional network but is selectively activated in white matter during encephalitic disease, highlighting region- and cell-type-targeted therapeutic opportunities.