**Background:** Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death globally, driven by dyslipidemia and inflammation. While statins are effective, they have side effects, prompting interest in complementary therapies from Traditional Chinese Medicine. Folium Artemisiae argyi (Artemisia argyi) contains bioactive compounds with anti-inflammatory properties, but its mechanisms in ASCVD are unclear. This study aimed to identify active compounds from Folium Artemisiae argyi and validate their anti-atherosclerotic effects using network pharmacology and in vitro experiments.
**Methods:** The study employed a multi-step approach. First, compounds from Folium Artemisiae argyi were identified using the TCMSP database, filtered by oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Target genes for these compounds were obtained from the SEA database, and atherosclerosis-related genes were sourced from MalaCards and OMIM databases. Overlapping genes (hub genes) were identified via Venn diagram. A protein-protein interaction (PPI) network was constructed using STRING, and KEGG pathway enrichment was performed with WebGestalt. GEO datasets (GSE9128, GSE71226) were used to validate differential expression of hub genes. Molecular docking (MOE software) assessed binding affinity of quercetin and naringenin to IL-1β, MMP9, and VEGFA. In vitro, Raw264.7 macrophages were stimulated with LPS (10 µg/ml) and treated with quercetin or naringenin (10, 20, 50 µM) for 24 h. mRNA expression of IL-6, IL-1β, and MMP9 was measured by qRT-PCR, and protein expression by Western blot. Statistical significance was set at p < 0.05.
**Key Results:** From 135 compounds, 9 met ADME criteria (OB ≥ 30%, DL ≥ 0.18), including quercetin (OB 46.43%, DL 0.28) and naringenin (as (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, OB 42.36%, DL 0.21). Eight hub genes were identified: IL-1β, MMP9, VEGFA, and others. KEGG analysis highlighted the "Fluid shear stress and atherosclerosis" pathway (p = 6.81E-08, FDR = 3.57E-06). GEO validation showed IL-1β (log FC = 1.20, p = 0.009) and MMP9 (log FC = 2.27, p = 0.019) were upregulated, while VEGFA was downregulated (log FC = -1.69, p = 0.001). Molecular docking revealed strong binding: quercetin with MMP9 (-6.03 kcal/mol), IL-1β (-5.10 kcal/mol), VEGFA (-5.48 kcal/mol); naringenin with MMP9 (-6.61 kcal/mol), IL-1β (-5.34 kcal/mol), VEGFA (-5.51 kcal/mol). In vitro, LPS significantly increased IL-6, IL-1β, and MMP9 mRNA and protein (p < 0.0001). Quercetin and naringenin dose-dependently reduced these levels. For example, quercetin 10 µM vs. LPS for IL-6: p < 0.0001; naringenin 10 µM vs. LPS for IL-1β: p < 0.0001; quercetin 10 µM vs. LPS for MMP9: p = 0.0076; naringenin 20 µM vs. LPS for MMP9: p = 0.0035.
**Clinical Implications:** This study provides preclinical evidence that quercetin and naringenin from Folium Artemisiae argyi have anti-inflammatory effects by suppressing IL-1β and MMP9, key drivers of atherosclerosis. The findings support the potential of these flavonoids as adjunctive therapies for ASCVD, particularly for patients who cannot tolerate statins. However, the results are limited to in vitro models, and further in vivo studies and clinical trials are needed to confirm efficacy and safety in humans.