Multifaceted Mechanisms of Plant Metabolites in Pulmonary Arterial Hypertension: A Critical Review Beyond Vasodilation

Jun-Jun Li¹Chen-Yan Hu²Jia-Hui Zhu^3*Ruolan Li^4*

• ¹Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Sichuan Cancer Hospital and Institute, Chengdu, China
• ²Department of Laboratory Medicine, Medical Center Hospital of Qionglai City, Medical Center Hospital of Qionglai City, Chengdu, China
• ³Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Sichuan Cancer Hospital and Institute, Chengdu, China
• ⁴Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan Cancer Hospital and Institute, Chengdu, China

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling, inflammation, and metabolic dysregulation. Current pharmacotherapies primarily target vasodilation but fail to reverse structural remodeling or arrest disease progression. Plant metabolites have been proposed as potential therapeutic leads due to their structural diversity and reported multi‑target actions; however, their safety and efficacy profiles in PAH remain incompletely validated. Beyond vasodilation, plant metabolites have been reported to modulate vascular remodeling, inflammation, oxidative stress, cellular metabolism, and epigenetic regulation, predominantly in preclinical models. However, most supporting evidence remains preclinical, often derived from rodent models and high-concentration in vitro assays, with limited validation of direct target engagement and clinical translatability. This review critically evaluates the multifaceted mechanisms of plant metabolites in PAH beyond vasodilation, with an explicit focus on the quality of evidence, the relevance of preclinical models, and the significant confounding issue of pan-assay interference compounds (PAINS). We highlight that while many metabolites show promising multi-target effects in vitro and in rodent models, the translational potential of most is severely limited by unvalidated target engagement, poor pharmacokinetics, and a lack of rigorous clinical data.