Unveiling the protective mechanisms of Pipa Qingfei Decoction in pulmonary arterial hypertension: Insights from network pharmacology, metabolomics and Mendelian randomization.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Pipa Qingfei Decoction (PQD) is a classical prescription that has been widely used in traditional Chinese medicine (TCM) for thousands of years. However, no evidence supports PQD as an effective prescription for pulmonary artery hypertension (PAH) treatment. AIM OF THE STUDY: This study aims to explore the protective potential and mechanisms of PQD against PAH. MATERIALS AND METHODS: A monocrotaline (MCT)-induced rat model was established to evaluate PQD's protective effects against PAH. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to characterize the active ingredients of PQD. Network pharmacology and metabolomics were used to determine potential pathways and targets. Mendelian randomization (MR) validated causal associations. Ultra-High-Performance Liquid Chromatography Mass Spectrometer (UHPLC-MS/MS) was employed to analyze metabolite levels in PAH rats. RESULTS: PQD could prevent PAH by attenuating abnormal proliferation. Moreover, multiple compounds and targets were identified contributing to PQD against PAH. Integrated analysis of network pharmacology and metabolomics revealed that amino acid metabolism was involved in PQD protecting PAH. MR analysis confirmed that amino acid metabolism may be the pivotal factor affecting the progression of PAH. Particularly, aspartate and glutamate metabolism disturbances in PAH rats were significantly modulated by PQD. CONCLUSIONS: This study points to a novel mechanism that PQD could effectively prevent PAH by regulating the aspartate and glutamate metabolic disturbances through targeting related regulatory enzymes. These findings expand the clinical application of PQD and propose an appealing strategy for guiding the precision medicine of PAH.