Synergistic disruption of blood-brain barrier and neuroimmune homeostasis by sleep-related environmental pollutants drives sleep disorders: an integrated computational and experimental study

Environmental pollutants are increasingly linked to sleep disorders (SD), affecting 27% of people globally, yet their synergistic effects remain understudied. Network toxicology identified 252 shared targets between sleep-related environmental pollutants (SREPs: NO₂, formaldehyde, benzene) and SD. PPI network and diagnostic model identified four hub genes (HSP90AA1, RELA, PTGS2, MMP9) with moderate-to-high predictive value (AUC: 0.708-0.979). Immune infiltration analysis showing elevated T cells and reduced astrocytes and neurons in patients with SD. Molecular simulations confirmed stable SREP-hub protein binding, with benzene exhibiting the highest affinity. Crucially, mixed SREPs exposure induced more severe toxicity than individual pollutants, demonstrating true synergistic disruption. In vivo, SREPs metabolites disrupted sleep architecture, impaired the blood-brain barrier (BBB), and induced neurobehavioral deficits. In vitro studies using brain endothelial cells (BMVECs) revealed that SREPs directly increase permeability, suppress tight junctions, and activate a pro-inflammatory cascade involving NF-κB signaling, enhanced MMP9 activity, and prostaglandin E2 synthesis. Curcumin intervention effectively counteracted these effects, restoring BBB integrity, normalizing sleep patterns, and suppressing hub gene expression and neuroinflammation in vivo and in vitro by targeting the identified hub gene network. Our integrated computational-experimental strategy establishes a novel "pollutant-BBB-neuroimmune-sleep" axis, providing a mechanistic framework for assessing cumulative environmental risks and advancing targeted interventions.