Polystyrene nanoplastics induce hepatic steatosis by disrupting autophagic degradation of NCoR1 and suppressing PPARα-mediated fatty acid oxidation.

Micro- and nanoplastic (MNP) pollution is a global public health concern, with inevitable ingestion by humans. The liver functions as a primary target organ, and studies have confirmed the presence of microplastics in human hepatic tissues. However, the hepatotoxic effects resulting from such exposure remain poorly characterized. Although polystyrene nanoplastics (PSNPs) have been implicated in disrupting hepatic lipid homeostasis and inducing steatosis, the underlying molecular mechanisms remain elusive. In this study, C57BL/6J mice were gavaged with PSNPs to establish an in vivo exposure model. Histopathological analysis demonstrated that exposure to PSNPs, in conjunction with a high-fat diet (HFD), facilitated the development of a hepatic steatotic phenotype. Multi-omics analysis revealed significant suppression of the PPARα signaling pathway, mechanistically linked to impaired fatty acid β-oxidation. Further experiments demonstrated that PSNPs inhibited the autophagic degradation of NCoR1. Concurrently, PSNP exposure activated the mTOR/S6K2 signaling pathway, promoting NCoR1 phosphorylation and nuclear translocation, thereby suppressing PPARα-regulated expression of genes involved in fatty acid β-oxidation, ultimately leading to hepatic lipid accumulation. Overall, this study elucidates the molecular mechanism by which PSNPs induce hepatic steatosis through NCoR1 dysregulation, providing a theoretical foundation for nanoplastic-related hepatotoxicity research and advancing health risk assessment related to MNP pollution.