The underexplored pulmonary toxicity of pyrrolizidine alkaloids: Emerging hazard from food contamination.

Pyrrolizidine alkaloids (PAs) are the most widespread plant-derived toxins globally. Humans are frequently exposed to PAs through ingestion of PA-contaminated food products, with chronic dietary exposure estimated at up to 48.4 ng/kg body weight/day, posing a significant global health threat. Aside from the well-documented hepatotoxicity, dietary exposure to PAs is strongly implicated in the development of pulmonary arterial hypertension (PAH), a serious and often fatal disease with limited treatment options. However, the underlying molecular mechanisms remain poorly defined. This review provided updated information of PA contamination in representative food and herbal products. For PAs' characterized toxic effects on pulmonary vasculature, our review shifts previous focus from downstream pathological processes to the etiological role of dietary PA exposure in PAH development. The activation of pulmonary arterial endothelial cells (PAECs), together with vasoconstriction, inflammation, and vascular remodeling, is recognized as an early event in PAH pathogenesis. Subsequently, activated immune cells, platelets, and dysfunctional PAECs release a complex array of growth factors, inducing pulmonary vascular remodeling and PAH progression. By reviewing intoxication targets and molecular pathways, we propose potentially novel therapeutic targets for dietary PA-related PAH. Given the ubiquitous distribution in the global food chain and their underexplored link to cardiopulmonary disease, we also provide perspectives and outlooks of preventive strategies and targeted interventions.