Polystyrene microplastic uptake drives Inflammatory, Epitranscriptomic, and Metabolic Reprogramming in Human Aortic Endothelial cells

Microplastics (MPLs) are pervasive environmental pollutants increasingly linked to adverse human health outcomes, including atherosclerosis. However, the underlying mechanisms remain poorly understood. Human aortic endothelial cells (HAECs), which line the inner surface of blood vessels, play a critical role in maintaining vascular homeostasis and in the development of atherosclerosis. This study demonstrates that polystyrene microplastics enter HAECs through clathrin-mediated endocytosis and macropinocytosis and subsequently co-localize with mitochondria and lysosomes. Exposure to MPLs induced coordinated transcriptional, epitranscriptomic, and metabolomic reprogramming in HAECs. Transcriptomic analysis revealed disruption of mitochondrial genes and activation of inflammatory pathways with the response of the NF-{kappa}B pathway being particularly prominent. Mass spectrometry analysis of RNA modification further identified significant remodeling of the epitranscriptomic landscape, highlighted by increased 1-methyladenosine (m1A) modification and reciprocal regulation of its associated enzymes (TRMT61A upregulation and ALKBH3 suppression), along with alterations in other RNA modifications such as m3C, pseudouridine ({Psi}), m5C, and m7G. Comparative analysis of transcriptomic profiles from human atherosclerotic plaques revealed shared dysregulated pathways in vascular regulation and cellular signaling. Metabolomic profiling further showed extensive remodeling of lipid metabolic networks associated with oxidative stress and inflammation. Together, these findings suggest that MPLs exposure may disrupt endothelial function and pose a potential risk to human cardiovascular health. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/737624v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@2ad601org.highwire.dtl.DTLVardef@47f041org.highwire.dtl.DTLVardef@ee45cdorg.highwire.dtl.DTLVardef@128d6d5_HPS_FORMAT_FIGEXP M_FIG C_FIG