Unraveling hepatotoxicity: mechanistic insights into food chain-transferred nanoplastics disrupting PPAR signaling and liver metabolism

Against the backdrop of increasing global plastic consumption, nanoplastics (NPs) formed from the degradation of plastic waste have become widespread in ecological media. These particles can transfer through the food chain to higher trophic organisms, accumulating in organs and posing a health risk. As the primary metabolic organ for ingested NPs, the liver demands urgent investigation into the toxicity mechanisms induced by these particles. Here, we employed a multi-omics-integrated approach to investigate the impact of food chain-transferred nanoplastics (FCT-NPs) on hepatic metabolic and detoxification functions in mice. Our findings demonstrated substantial enrichment of FCT-NPs in liver, resulting in histopathological damage, impaired liver function, and metabolic homeostasis disruption. Transcriptomic, proteomic, and metabolomic analyses collectively identified the suppression of peroxisome proliferator-activated receptor (PPAR) signaling pathway as a central mechanism of FCT-NPs-induced hepatotoxicity. Molecular docking and dynamics simulations revealed a potential direct interaction site between NPs and the PPAR ligand-binding domain, suggesting a mechanistic basis for toxicity. Specifically, inhibition of the PPAR pathway downregulated key downstream processes, disrupting fatty acid transport and metabolism, retinoid and steroid metabolism, and redox balance. This study provides the first mechanistic evidence linking dietary FCT-NPs exposure to PPAR interaction and metabolic dysfunction, thereby advancing risk assessment for NPs-induced liver injury in both mammals and humans.