Bioactive Constituents and Antihypertensive Mechanisms of Zhengan Xifeng Decoction: Insights from Plasma UPLC–MS, Network Pharmacology and Molecular Dynamics Simulations

<b>Background/Objectives</b>: Hypertension is a global health challenge. Zhengan Xifeng Decoction (ZXD), a classical traditional Chinese medicine, has shown clinical efficacy against hypertension. This study aimed to identify the bioactive constituents of ZXD and elucidate its antihypertensive mechanisms by integrating plasma UPLC-MS (ultra-performance liquid chromatography-mass spectrometry) analysis, network pharmacology, and molecular dynamics (MD) simulations. <b>Methods</b>: ZXD constituents and plasma-absorbed compounds were characterized by UPLC-MS. Putative targets (TCMSP, SwissTargetPrediction) were cross-referenced with hypertension targets (GeneCards, OMIM) and analyzed in a STRING protein-protein interaction network (Cytoscape) to define hub targets, followed by GO/KEGG enrichment. Selected protein-ligand complexes underwent docking, Prime MM-GBSA calculation, and MD validation. <b>Results</b>: A total of 72 absorbed components were identified, including 14 prototype compounds and 58 metabolites. Network pharmacology identified ten key bioactive compounds (e.g., liquiritigenin, isoliquiritigenin, and caffeic acid), 149 hypertension-related targets, and ten core targets such as SRC, PIK3CA, PIK3CB, EGFR, and IGF1R. Functional enrichment implicated cardiovascular, metabolic, and stress-response pathways in the antihypertensive effects of ZXD. Molecular docking demonstrated strong interactions between key compounds, including liquiritigenin, caffeic acid, and isoliquiritigenin, and core targets, supported by the MM-GBSA binding free energy estimation. Subsequent MD simulations confirmed the docking poses and validated the stability of the protein-ligand complexes over time. <b>Conclusions</b>: These findings provide mechanistic insights into the multi-component, multi-target, and multi-pathway therapeutic effects of ZXD, offering a scientific basis for its clinical use and potential guidance for future drug development in hypertension management.