The vascular protective effects of Perillae folium in hyperlipidemia: An integrated strategy integrating metabolomics, network pharmacology and <em>in vitro</em> / <em>in vivo</em> validation

Dietary intervention is a reliable approach to protect high-risk individuals against cardiovascular events. Perillae folium (PF) in China is valued for its medicinal, nutritional, and economic benefits, particularly in managing diet-induced lipid metabolism disorders. However, unclear active constituents and mechanisms hinder its quality control and resource utilization. In this study, notable regional variations in the compound profiles of samples sourced from different areas were uncovered in qualitative and quantitative analyses. A comprehensive strategy was implemented, integrating network pharmacology, metabolomics, and experimental validations conducted both <em>in vivo</em> and <em>in vitro</em>, to investigate potential active compounds and mechanisms of action. Four compounds (apigenin-7-<em>O</em>-diglucuronide, shisonin, scutellarin, and rosmarinic acid) were identified as the primary active constituents. PF demonstrated cardiovascular protective effects by modulating the arginine biosynthesis pathway to increase the availability of <em>L</em>-arginine, as well as activating the PI3K-AKT1 signaling pathway, thereby facilitating the release of nitric oxide (NO).