Zang Siwei Qingfei Mixture Alleviates Pulmonary Arterial Hypertension in Rats: Integrated Network Pharmacology and Metabolomics

Purpose: Pulmonary arterial hypertension (PAH) is a fatal condition characterized by poor control of pulmonary hemodynamics and vascular development. Zang Siwei Qingfei mixture (ZSQM) is a traditional Chinese medicine formula used for the treatment of chronic respiratory diseases. However, the underlying mechanism of ZSQM for treating PAH remains unclear.

Methods: A PAH rat model was established after monocrotaline (MCT) injection, and pulmonary hemodynamic features and pathological changes were evaluated. The candidate targets of ZSQM against PAH were discovered using network pharmacology. Then, molecular docking was used to validate the discovered key targets. Moreover, serum metabolomics was used to identify differential metabolites. The metabolomics and network pharmacology integrated network was constructed.

Results: ZSQM alleviated MCT-induced pulmonary vascular injury and vascular remodeling. We found ZSQM core component chrysin and six hub genes according to network pharmacology, including CYP2C19, CASP8, PTK2, VEGFA, FLT4, and TNNI3. Molecular docking revealed strong binding affinities between key targets and chrysin. Meanwhile, western blotting results validated significant changes in the expression of these key targets. Subsequently, we confirmed that chrysin existed in the ZSQM by HPLC–MS. In addition, a total of 19 metabolites with potential significance were identified to be implicated in the therapeutic mechanisms of ZSQM. The further integrated analysis indicated an interconnection between these key targets, their related core metabolites (12(S)HETE, ascorbate, succinate, vitamin C, and L-arginine), and metabolic pathways.

Conclusion: The study, employing metabolomics and network pharmacology, has concluded that ZSQM has the potential to enhance the treatment of PAH by targeting multiple pathways and molecular targets. This finding suggests that ZSQM could serve as a promising alternative therapy for PAH.