Molecular mechanism differences between nanoplastics and microplastics in colon toxicity: nanoplastics induce ferroptosis-mediated immunogenic cell death, while microplastics cause cell metabolic reprogramming.

This study investigates the size-dependent mechanisms by which polystyrene (PS) microplastics (MPs) cause intestinal epithelial injury, focusing on the differential effects of nanoscale (100 nm) and microscale (10 μm) particles. Using both cellular and animal models, we found that 100 nm MPs are internalized by intestinal epithelial cells via endocytosis, triggering oxidative stress and ferroptosis, while 10 μm MPs primarily induce epithelial damage through mechanical disruption and metabolic reprogramming. Proteomic analyses revealed that small MPs significantly upregulate ferroptosis-related genes, including Fosl1 and components of the p53 pathway. Functional studies showed that Fosl1 promotes p53 transcription, suppresses Slc7a11, and contributes to ferroptosis. Mechanistically, ferroptosis was characterized by intracellular iron accumulation, glutathione (GSH) depletion, GPX4 inactivation, and excessive lipid peroxidation. Treatment with Ferrostatin-1 or Fosl1 knockdown alleviated ferroptosis and epithelial injury. In contrast, large MPs activated the mechanosensitive YAP pathway, leading to cytoskeletal remodeling and a metabolic shift from oxidative phosphorylation to anaerobic glycolysis. This metabolic reprogramming was associated with increased inflammation. These findings demonstrate that microplastic particle size critically determines toxicity mechanisms—ferroptosis for small particles and YAP-mediated metabolic disruption for large ones—and suggest potential therapeutic targets for mitigating microplastic-induced intestinal damage. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-025-03545-1.