Polystyrene Microplastics Exacerbate Mitochondrial Damage by Inhibiting PTK6-Dependent Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease

The toxic mechanisms of microplastics (MPs), which are emerging environmental pollutants, remain uncertain. MPs have been linked to severe liver metabolic disorders; however, the underlying mechanisms remain unclear. In this study, we found that the plasma concentrations of MPs, especially polystyrene MPs (PS-MPs), were higher in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) than in healthy controls and showed a positive correlation with liver enzymes and serum lipids, as detected by pyrolysis gas chromatography-mass spectrometry. Exposure to PS-MPs of 2 um in size resulted in a significant increase in the severity of fibrosis and inflammation and exacerbated mitochondrial dysfunction and mitophagy disorders in livers of db/db mice and palmitic acid (PA)-treated HepG2 cells. RNA sequencing and proteomics analyses demonstrated that the mitophagy and the autophagy-related protein tyrosine kinase 6 (PTK6) underwent significant changes. Molecular docking, surface plasmon resonance (SPR), and molecular dynamics studies confirmed that PS-MPs stably interacted with PTK6. Furthermore, when PTK6 was silenced, PS-MPs treatment failed to exacerbate mitophagy in PA-treated HepG2 cells and PS-MPs inhibited mitophagy in mitophagy agonist CCCP-stimulated HepG2 cells. Collectively, these findings suggest that PS-MPs exacerbate liver damage and mitochondrial damage via PTK6-mediated mitophagy in MASLD, providing valuable insights into the hepatotoxic effects of MPs on human liver health and suggesting potential therapeutic targets for MASLD.