Polystyrene nanoplastics trigger ferroptosis in Nrf2-deficient gut via ether phospholipid accumulation

The widespread environmental presence of nanoplastics (NPs) raises significant concerns about their health impacts, particularly on the gastrointestinal system, as NPs are primarily ingested. While previous studies have linked NP-induced intestinal toxicity to oxidative stress and reactive oxygen species (ROS) accumulation, the specific mechanisms of cell death remain unclear. Here, we showed that environmentally relevant concentrations of polystyrene nanoplastics (PS-NPs) induced ferroptosis, a form of lipid peroxidation-driven cell death, in intestinal epithelial cells. Using intestinal epithelial-specific Nrf2-deficient mice (Nrf2^fl/fl-Vil^Cre+) and human intestinal epithelial Caco-2 cells, we demonstrated that Nrf2, a key oxidative stress regulator, play a protective role against PS-NP-induced ferroptosis. PS-NP exposure disrupted ether phospholipid metabolism, leading to the accumulation of polyunsaturated fatty acid-ether phospholipids and heightened lipid peroxidation in the intestines of Nrf2^fl/fl-Vil^Cre+ mice. This accumulation increased the susceptibility of intestinal epithelial cells to ferroptosis. Additionally, a high-fat diet further exacerbated this effect, suggesting that individuals with reduced NRF2 activity and poor dietary habits may be especially vulnerable to PS-NP-induced intestinal damage. Our findings offered new insights into the molecular mechanisms of NP-induced intestinal toxicity and underscored the health risks posed by environmental PS-NP exposure, particularly in populations with compromised antioxidant defenses.