Abstract

The modified Taohong Siwu decoction (MTHSWD), a traditional prescription, demonstrates notable efficacy in treating cardiovascular diseases. However, its potential mechanisms in addressing atherosclerosis (AS) require further exploration. Investigating the underlying mechanisms of MTHSWD in treating AS is imperative. AS mouse models received MTHSWD treatment, with vascular pathology and fibrosis assessed through histopathological staining. Network pharmacology identified bioactive components and potential targets, followed by molecular docking verification of key compound-target interactions. Biochemical validation included Western blot analysis. MTHSWD significantly ameliorated vascular structural abnormalities and fibrosis in AS models. Network pharmacology analysis revealed 133 active components targeting 295 proteins, intersecting with 3309 AS-related genes to form 191 overlapping targets. Twenty-two components (e.g., quercetin) demonstrated multi-target activity (≥ 15 targets). PPI network topology identified 32 hub targets including AKT1, MAPK1/8/14. Functional analysis showed that apoptosis, MAPK signaling, and lipid metabolism pathways were significantly enriched. The pathway-target network highlighted AKT1 and MAPK family members as central regulators. Molecular docking confirmed strong interactions (binding energy < −9.0 kcal/mol) between AKT1-stigmasterol/anhydroicaritin, MAPK1-emodin, and MAPK8/14-β-carotene. Experimental validation demonstrated MTHSWD’s regulation of AKT1, MAPK1/14, cleaved-caspase-3, and Bcl-2 expression, enhancing endothelial viability while suppressing apoptosis. This integrated approach reveals that MTHSWD exerts anti-AS effects through multi-target modulation of PI3K/AKT and MAPK signaling pathways, promoting endothelial survival and attenuating apoptotic processes, ultimately alleviating AS-related vascular pathology.