Multifaceted mechanisms of plant metabolites in pulmonary arterial hypertension: a critical review beyond vasodilation

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 <i>in vitro</i> 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 <i>in vitro</i> 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.