Leveraging Untargeted Metabolomics and Molecular Dynamics Simulation Unraveling the Multi-Target Mechanism of Taohong Siwu Decoction against Pulmonary Hypertension.

INTRODUCTION: Pulmonary hypertension (PH) is a complex disease with diverse etiologies and limited treatment options. Taohong Siwu Decoction (THSWD), a traditional Chinese medicine formula, has shown potential therapeutic benefits for PH, yet its underlying pharmacological mechanisms remain poorly defined. This study aimed to systematically investigate the specific mechanisms through which THSWD exerts its anti-PH effects using an integrated pharmacological strategy.

METHODS: We employed a comprehensive approach combining in vivo experimentation and multi-omics analysis. A rat model of PH was established to evaluate the therapeutic effects of THSWD. Hemodynamic parameters, pulmonary vascular remodeling, and right ventricular hypertrophy were assessed. Key markers of proliferation (PCNA) and inflammation (NF-κB, CD68) were analyzed. Furthermore, network pharmacology was utilized to identify potential active ingredients and core targets, which were validated through molecular docking and molecular dynamics simulations. Untargeted metabolomics was conducted to identify associated metabolic biomarkers and pathways.

RESULTS: Treatment with THSWD significantly ameliorated PH progression, as evidenced by reduced right ventricular systolic pressure, attenuated pulmonary vascular remodeling, and decreased right ventricular hypertrophy in rat models. THSWD downregulated the expression of PCNA and suppressed inflammatory responses, indicated by reduced NF-κB activation and CD68 levels. Network pharmacology identified luteolin, quercetin, kaempferol, and β-sitosterol as key active components and highlighted the HIF-1α/VEGF signaling pathway as a central target. Molecular simulations confirmed stable binding between these components and HIF-1α/VEGFA, with particularly strong interactions observed for β-sitosterol-HIF-1α, quercetin-HIF-1α, and luteolin-VEGFA. Metabolomic analysis revealed that THSWD modulated metabolites, including 12-hydroxyicosanoic acid, 7-methylguanine, and lapachenole, suggesting involvement of the arachidonic acid metabolic pathway.

DISCUSSION: The findings indicate that THSWD mitigates PH through multi-target mechanisms, primarily by inhibiting HIF-1α/VEGF-mediated pulmonary vascular remodeling and right ventricular hypertrophy, and by modulating arachidonic acid metabolism to restore metabolic homeostasis. The study provides a mechanistic link between the formula's traditional use and modern pharmacological actions, highlighting its potential as a multi-component therapy for PH.

CONCLUSION: THSWD effectively attenuates experimental PH by delaying pulmonary vascular remodeling and right ventricular hypertrophy. Its therapeutic effects are mediated through regulation of the HIF-1α/VEGFA signaling pathway and correction of metabolic imbalances in the arachidonic acid pathway. This integrated evidence supports the further development of THSWD as a promising therapeutic strategy for PH.