Cuscuta chinensis Lam. Ameliorates Pulmonary Arterial Hypertension via the PI3K/Akt/mTOR/HIF-1α Pathway: Evidence from Network Pharmacology and In Vivo Validation.

Abstract

Introduction: Pulmonary Arterial Hypertension (PAH) is a progressive and lifethreatening cardiopulmonary disorder, primarily characterized by sustained elevation of pulmonary vascular resistance and structural remodeling of pulmonary vessels, which eventually leads to right ventricular failure and death. Cuscuta chinensis Lam. (CCL), a traditional medicinal herb from Xinjiang, has been reported to exert cardiovascular protective effects, including antiinflammatory, antioxidant, and pro-apoptotic activities. Nevertheless, the precise pharmacological role of CCL in alleviating PAH and the molecular mechanisms underlying this effect remain largely unexplored.

Methods: The therapeutic efficacy of CCL was first evaluated in an MCT-induced rat model of PAH by measuring mean Pulmonary Artery Pressure (mPAP), mean Right Ventricular Pressure (mRVP), and pulmonary vascular remodeling. Network pharmacology was subsequently used to identify the potential bioactive compounds, candidate targets, and enriched signaling pathways associated with the observed therapeutic effects. Molecular docking was performed to evaluate the predicted interactions between the principal compounds and selected target proteins. Finally, the predicted PI3K/Akt/mTOR/HIF-1α pathway was examined using RT-qPCR and Western blotting.

Results: CCL treatment significantly reduced mPAP and mRVP, and ameliorated pulmonary arterial wall thickening and luminal narrowing in MCT-induced PAH rats. These findings provided direct in vivo evidence of CCL's therapeutic effects against experimental PAH. Subsequent network pharmacology identified 64 overlapping targets between CCL-associated and PAHassociated target sets, with quercetin and kaempferol emerging as principal candidate compounds. Enrichment and docking analyses implicated the PI3K/Akt/mTOR/HIF-1α signaling axis. Consistent with this prediction, CCL reduced PI3K and Akt phosphorylation and downregulated mTOR and HIF-1α expression in lung tissues.

Discussion: The study's findings demonstrate that CCL effectively ameliorates the core pathological features of PAH. These favorable outcomes are potentially associated with the suppression of inflammatory responses, the disruption of the PI3K/Akt/mTOR/HIF-1α pathway, and the prevention of structural vascular remodeling. Furthermore, although key regulatory targets were validated, the broader predicted interactome requires further experimental scrutiny.

Conclusion: This study revealed that CCL alleviates PAH potentially by suppressing the PI3K/Akt/mTOR/HIF-1α signaling pathway. This provides new insights into the identification and utilization of Xinjiang's distinctive medicinal plants for the treatment of PAH.