Identification of potential active ingredients from Chuanxiong Rhizoma in the treatment of vascular dementia: CHI3L1 and TLR2 are potential key targets

Vascular dementia (VaD) is a cognitive impairment resulting from cerebrovascular disease, which causes functional decline. Its rising prevalence and the absence of effective therapeutic interventions highlight an urgent need for novel therapeutic strategies. The research aimed to identify crucial target genes and bioactive compounds responsible for the therapeutic effects of Chuanxiong Rhizoma in VaD through a comprehensive bioinformatics strategy. Network pharmacology identified 240 shared target genes between Chuanxiong Rhizoma and VaD. Weighted gene co-expression network analysis identified 114 genes significantly associated with VaD. Venn analysis identified CHI3L1, TAC1, toll-like receptor 2 (TLR2), and CCL2 as candidate target genes. Differential expression analysis confirmed dysregulation of CHI3L1, TAC1, TLR2, and CCL2 in VaD. Single-cell RNA analysis showed CHI3L1 predominantly in fibrous astrocytes, TAC1 in Parvalbumin inhibitory neurons, and TLR2 in microglia. Receiver operating characteristic analysis showed CHI3L1 (area under the curve [AUC] = 0.6597, P = .0144), TAC1 (AUC = 0.7797, P < .0001), and TLR2 (AUC = 0.7468, P = .0002) had significant AUC values, indicating potential diagnostic value for VaD. Gene set enrichment analysis showed CHI3L1, TAC1, and TLR2 enriched in chemokine signaling, allograft rejection, and JAK/STAT pathways. Immune cell infiltration analysis indicated that the correlation of CHI3L1 with Macrophages M2 was significantly positive, whereas it was significantly negative with activated natural killer cells (NK cells). The correlation of TAC1 with Macrophages M2 was significantly negative, whereas it was significantly positive with both activated NK cells and follicular helper T cells. The correlation of TLR2 with Macrophages M2 was significantly positive, whereas it was significantly negative with activated NK cells and follicular helper T cells. Molecular docking followed by 100-nanosecond molecular dynamics simulations indicated that palmitic acid binds stably to both CHI3L1 and TLR2, and that perillyl alcohol binds stably to TLR2, whereas the CHI3L1-perillyl alcohol complex showed persistent instability during the molecular dynamics trajectory and was therefore not considered a supported interaction. The findings indicated Chuanxiong Rhizoma might exert its anti-VaD effects through palmitic acid and perillyl alcohol by targeting CHI3L1 and TLR2. The study generated a multi-component, multi-target hypothesis for VaD that warrants further experimental validation.