Unveiling Anti-atherosclerotic Targets of Perilla frutescens through a Multi-scale Computational Framework Integrating Network Pharmacology, Single-cell Analysis, Machine Learning, and Molecular Dynamics

Despite the widespread implementation of lipid-lowering therapy, the persistence of residual inflammatory risk, driven by immunometabolic network dysregulation, remains a cardinal therapeutic challenge in atherosclerosis (AS) management. While Perilla frutescens exhibits well-documented anti-inflammatory properties, the precise molecular targeting within the atherosclerotic plaque microenvironment and the regulatory mechanisms governing intercellular communication networks remain poorly elucidated. We established a multi-scale integrative computational framework synergizing network pharmacology, human atherosclerotic plaque single-cell transcriptomic (scRNA-seq) profiling, and ensemble machine learning algorithms (LASSO and random forest) for systematic identification of robust therapeutic targets. Molecular dynamics simulations validated the binding affinity and thermodynamic stability of drug–target complexes. We analyzed the cellular heterogeneity lineage of plaques were identified and a core feature set of 10 genes were identified which specifically mapped the differentiation trajectory of macrophages to foam cells. External validation in an independent cohort demonstrated superior diagnostic performance of this signature (AUC = 0.996). Cellular communication network dissection revealed the foam cell-driven SPP1–ITGB1 signaling axis as a pivotal conduit orchestrating inflammatory crosstalk. Molecular docking demonstrated pronounced binding affinity between luteolin, the principal bioactive constituent of Perilla frutescens , and ITGB1 (binding energy: −8.9 kcal/mol). Molecular dynamics simulations further corroborated the efficacy of luteolin in stabilizing ITGB1 conformation via a "conformational-locking" mechanism (RMSD equilibration within 0.10–0.20 nm), thereby abrogating pathological cell adhesion signaling transduction. Collectively, this study provides a high-resolution molecular atlas of Perilla frutescens -mediated AS intervention, systematically elucidating the mechanistic paradigm whereby luteolin attenuates vascular inflammation through targeted disruption of the SPP1–ITGB1 communication axis.