Mechanistic study on GANDouling tablet in the treatment of Wilson's disease with cognitive impairment based on network pharmacology and transcriptomic analysis.

BACKGROUND

Wilson's disease (WD) is a copper metabolism disorder often accompanied by cognitive impairment, yet effective interventions remain limited. Gandouling Tablet, a traditional Chinese herbal formula, has shown clinical efficacy in WD, but its mechanisms in cognitive dysfunction are unclear.

METHODS

Active compounds and putative targets of Gandouling Tablet were retrieved from TCMSP and SwissTargetPrediction. Disease-related genes were obtained from multiple databases, and transcriptomic data (GSE197406) were analyzed to identify differentially expressed genes (DEGs). Intersecting targets were subjected to protein-protein interaction (PPI) analysis, GO/KEGG enrichment, and compound-target-pathway network construction. Molecular docking was used to evaluate compound-target binding. Finally, APP protein levels in serum (ELISA) and DRD2 mRNA expression in PBMCs (qRT-PCR) were measured before and after 4 weeks of Gandouling Tablet treatment in 15 patients with WD-related cognitive impairment.

RESULTS

A total of 928 DEGs were identified, and intersection analysis yielded 25 potential therapeutic targets. PPI analysis highlighted hub genes including APP, DRD2, and F2. Enrichment analysis indicated pathways related to synaptic plasticity, PI3K-Akt signaling, and neuroinflammation. Molecular docking demonstrated stable binding affinities between representative compounds and hub targets. Clinical validation showed significantly increased APP protein levels and DRD2 mRNA expression after Gandouling Tablet treatment (P < 0.001), consistent with network predictions.

CONCLUSION

Gandouling Tablet may improve cognitive impairment in WD through a multi-component, multi-target, and multi-pathway mechanism, particularly involving APP and DRD2. This integrative study provides molecular evidence and clinical support for the therapeutic potential of Gandouling Tablet in WD-related cognitive impairment.