Polystyrene nanoplastics trigger mitochondrial and metabolic reprogramming in cardiomyocytes: Evidence from integrated transcriptomic and metabolomic analysis

Nanoplastics (NPs) are emerging environmental pollutants that can cross biological barriers due to their small size. Although numerous studies have investigated their effects in animal and cell models, multi-omics evaluations of their potential cardiovascular toxicity are still limited. To address this gap, we conducted a comprehensive assessment of polystyrene NPs (PS-NPs) using both in vitro and in vivo models. Human AC16 cardiomyocytes were exposed to PS-NPs and analyzed using RNA-seq, untargeted metabolomics, and functional assays. Transcriptomics revealed enrichment of mitochondrial-related genes and response to lipids, with pathways involving mitochondrial translation, ribosome function, and oxidative phosphorylation (OXPHOS). Bioenergetic profiling showed reduced basal and maximal oxygen consumption and ATP-linked respiration, accompanied by increased intracellular and mitochondrial reactive oxygen species (ROS). Untargeted metabolomics indicated broad lipid remodeling, particularly in glycerophospholipids, and alterations in nucleotide metabolism, consistent with energy dysregulation. For in vivo validation, mice received repeated tail vein injections of PS-NPs every 3 days for 2 weeks. Electron microscopy showed PS-NPs accumulation in cardiomyocytes and mitochondrial cristae disruption. Echocardiography revealed interventricular septal thickening with preserved ejection fraction and fractional shortening, suggesting subclinical remodeling. Myocardial ATP content decreased, and western blotting showed downregulation of OXPHOS complexes III-V and Pgc-1α. Although the chemical and particulate effects could not be distinguished in this study due to the lack of a particulate control, these results indicate that PS-NPs impair mitochondrial function and energy homeostasis in cardiomyocytes, suggesting potential cardiovascular hazards and highlighting the need for exposure monitoring in risk assessment.