Gene Expression Omnibus database analysis reveals comorbidity mechanisms of type 2 diabetes mellitus and vascular dementia and predicts potential herbal therapeutics

Abstract Objective This study aimed to investigate the comorbid mechanisms linking type 2 diabetes mellitus (T2DM) and vascular dementia (VaD), focusing on the roles of astrocytes and neurons, and to identify potential therapeutic traditional Chinese medicines (TCMs) and compounds. Methods T2DM (GSE161355) and VaD (GSE122063) transcriptomic datasets were retrieved from the Gene Expression Omnibus database. Differential expression analysis, functional enrichment, and druggability assessment were conducted to identify potential core targets. Corresponding TCMs and compounds were predicted by using the TCMSP and HERB databases, followed by analyses of their pharmacokinetics, toxicity, and binding affinity. Results In astrocytes, eight core genes (e.g., HSP90AA1, HIF1A, PTEN) were identified and primarily enriched in autophagy and inflammatory pathways. Eight TCMs, including Corydalis yanhusuo and Phellodendron chinense , were predicted to be relevant. Indigo exhibited a relatively strong binding affinity to HSP90AA1 (−10.0 kcal/mol). In neurons, eight core genes (e.g., NFKB1, CYCS, PTGS2) were enriched in apoptosis and neuroinflammation pathways. Potential TCMs, such as Tripterygium wilfordii , were identified. Palmatine showed a relatively strong binding affinity to PTGS2 (−8.1 kcal/mol). Most predicted TCMs were characterized as bitter and cold in property, associated with the liver meridian, and attributed with heat‐clearing effects. Conclusion Our findings suggest that the comorbidity of T2DM and VaD may involve dysregulated inflammatory and apoptotic pathways in astrocytes and neurons. The predicted TCMs and compounds represent multitarget intervention candidates, consistent with TCM theories of “Yin deficiency with internal heat” and “phlegm‐stasis transforming into heat.” These findings provide a theoretical basis for future experimental validation and the development of TCM‐based therapies.