Chronic Nanoplastic Exposure Promotes the Development and Progression of Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT Background and Aims Plastic particles are a global pollution problem, and humans are potentially exposed to them. Ingested plastic particles, microparticles (MPs) and nanoparticles (NPs), predominantly accumulate in the liver and cause hepatotoxicity through oxidative stress and metabolic dysfunction. NPs promote more toxic actions than MPs; however, the mechanisms involved in developing and progressing metabolic dysfunction‐associated steatotic liver disease (MASLD) from chronic exposure to NPs remain poorly understood. Hedgehog (Hh) signalling regulates MASLD pathogenesis. Herein, we investigated the pathophysiological effects of NPs in MASLD. Methods Mice were orally administered NPs via drinking water while fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) for 12 weeks. Results NPs increased lipid accumulation in hepatocytes and apoptosis. Moreover, these actions were enhanced in lipotoxicity‐exposed hepatocytes. Chronically exposed NPs accumulated in mice livers and aggravated CDAHFD‐induced hepatic damage, especially fibrosis. Activated Hh signalling in the CDAHFD group was elevated by NP treatment. Increased Sonic Hh expression in the hepatocytes of NP‐treated mice in the CDAHFD group triggered Hh signalling in hepatic stellate cells (HSCs), which promoted liver fibrosis. Conclusions These results demonstrate that chronic exposure to NPs increases vulnerability to MASLD progression, suggesting that NPs are a potentially harmful factor in the development and progression of liver disease.