6PPD-quinone exposure and Alzheimer's disease: insights from integrative network pharmacology, transcriptomics,...

To systematically investigate the molecular associations between 6PPD-quinone (6PPD-Q), an environmental transformation product of the tire antioxidant 6PPD, and Alzheimer's disease (AD) pathogenesis.

An integrative strategy combining network pharmacology, transcriptomic validation, and machine learning was employed. Intersecting targets were identified through multi-database mining, followed by functional enrichment and protein-protein interaction (PPI) network analyses. Transcriptomic validation, SHAP-based XGBoost analysis, Mendelian randomization, and molecular docking were performed to evaluate target expression, diagnostic value, causal associations, and binding affinities.

A total of 92 intersecting targets were identified, enriched in synaptic structures, kinase activity, neuroinflammation, and apoptotic pathways. PPI analysis revealed 23 core targets, with NFKB1, GSK3B, and PIK3CA as key hub genes enriched in the cerebral cortex and basal ganglia. Transcriptomic data confirmed differential expression of core targets in AD. SHAP analysis identified PTGS2, KIT, PIK3CA, NFE2L2, and NFKB1 as high-value diagnostic predictors. Mendelian randomization supported a causal association between NFKB1 brain expression and AD risk. Molecular docking confirmed strong binding of 6PPD-Q to PTGS2, GSK3B, and NFE2L2.

This study provides the first systematic characterization of the molecular mechanisms by which 6PPD-Q may contribute to AD pathogenesis, potentially through inducing oxidative stress, activating neuroinflammation, and disrupting kinase signaling networks.