Network Pharmacological Exploration of Traditional Prescriptions for Hyperlipidemia-Associated Vascular Dementia toward Preclinical Candidate Selection

Objectives: Vascular dementia (VaD) is the second most common form of dementia worldwide, yet no disease-modifying therapies are currently available. Hyperlipidemia is a major modifiable risk factor contributing to VaD pathogenesis. This study aimed to explore the therapeutic potential of traditional herbal medicines for hyperlipidemia-associated VaD using an integrative network pharmacology approach. Methods: Prescriptions were retrieved from the traditional Chinese medicine (TCM) Information Database and cross-referenced with the pharmacopoeia of China and Taiwan. Disease-prescription-herb networks were constructed using Cytoscape. Therapeutic targets for hyperlipidemia and VaD were identified from the Therapeutic Target Database and mapped to herbal candidates via the TCM Systems Pharmacology Database and Analysis Platform. Network integration was performed to identify overlapping herbs with multi-target potential. Results: Analysis revealed convergence between hyperlipidemia and dementia prescriptions, with Dengzhanshengmai-jiaonang identified as a shared formulation. Core herbs such as Salviae Miltiorrhizae Radix, Crataegi Fructus, and Puerariae Radix were highly connected across both conditions. Target-herb network analysis identified peroxisome proliferator -activated receptor alpha, apolipoprotein A, and insulin-like growth factor-binding protein 3 as key therapeutic nodes. A total of 23 herbs were predicted to act on all three targets simultaneously. Notably, Nelumbinis Folium, Carthami Flos, and Eucommiae Cortex demonstrated overlapping activity, while dementia-specific herbs including Schisandrae Fructus, Ginseng Radix, and Gastrodiae Rhizoma were highlighted for neuroprotective potential. Conclusions: This integrative network pharmacology study demonstrates that traditional herbal medicines possess multi-target activity relevant to both metabolic and neurovascular pathways. The findings provide a rational basis for developing optimized herbal combinations as novel therapeutic strategies for hyperlipidemia-induced VaD, bridging traditional knowledge with modern pharmacological insights.