Review of plant-derived metabolites in atherosclerosis notes uneven evidence and assay interference

Atherosclerosis is a chronic inflammatory vascular disease in which dyslipidemia, endothelial dysfunction, and maladaptive innate immunity jointly drive plaque initiation, progression, and rupture. Among the innate immune mechanisms involved, neutrophil extracellular traps (NETs) have emerged as important amplifiers of endothelial injury, macrophage activation, necrotic core expansion, and immunothrombosis. These findings suggest that restoration of NET homeostasis may help attenuate atherosclerotic progression. Accordingly, plant-derived metabolites have attracted increasing attention because some of them reduce NET-associated readouts in cellular and preclinical models. However, the current evidence base remains uneven. For many polyphenols and flavonoids, the reported anti-NET activity is derived mainly from simplified in vitro systems and may be confounded by pan-assay interference compounds (PAINS)-like assay interference. Therefore, statistically significant reductions in extracellular DNA, reactive oxygen species (ROS), or myeloperoxidase (MPO)-related signals should not be overinterpreted as evidence of selective NET inhibition or clinically relevant efficacy in humans. At present, most plant-derived metabolites should be regarded as hypothesis-generating candidates rather than validated therapeutics. This review summarizes the contribution of NETs to atherosclerosis, critically appraises the pharmacological and translational strength of the available literature on these metabolites, and outlines future directions based on orthogonal NET assays, disease-relevant models, pharmacokinetic grounding, and biomarker-guided clinical studies.