Molecular mechanisms of diquat-induced brain injury: Insights from network toxicology and single-cell RNA sequencing

Objective

This study investigates the molecular mechanisms of diquat (DQ)-induced brain injury through an integrative approach combining network toxicology, single-cell RNA sequencing, and molecular docking technologies.

Methods

DQ target genes were predicted using the STITCH and SwissTargetPrediction databases, while brain injury-related genes were identified from the GeneCards, OMIM, and TTD databases. GO and KEGG enrichment analyses were conducted on the intersected genes. Core targets were identified through PPI network construction and visualization using Cytoscape software. The expression patterns of these core targets in brain tissue were analyzed using single-cell sequencing data from the PanglaoDB database. Finally, molecular docking was performed to validate the binding affinity between DQ and the core targets.

Results

Five core targets (PTGS2, NFE2L2, HMOX1, MAOB, and MAOA) were identified, showing significant involvement in oxidative stress, inflammatory response, and neurotransmitter metabolism pathways. Single-cell RNA sequencing confirmed their expression in brain tissue, providing cellular insights into DQ toxicity mechanisms. Molecular docking revealed strong binding affinities between DQ and these targets, particularly NFE2L2 (< −40 kcal/mol). In summary, PTGS2 likely amplifies inflammation, whereas NFE2L2 dysfunction may impair antioxidant defense, exacerbating oxidative stress. Similarly, HMOX1 inhibition could diminish cytoprotective effects, aggravating oxidative damage. Altered activities of MAOA and MAOB may disrupt neurotransmitter metabolism, amplifying oxidative stress and neuroinflammation.

Conclusion

DQ induces brain injury by disrupting redox balance, amplifying inflammation, and interfering with neurotransmitter metabolism. These findings enhance the understanding of DQ-induced brain injury and provide a theoretical foundation for developing potential therapeutic strategies and conducting environmental toxicity assessments.