Realistic-NPs trigger depression-like behaviors via mitochondrial iron overload mediating ferroptosis

ENVIRONMENTAL MICRO: and nanoplastics pose emerging neurotoxic risks, yet few studies have used environmentally realistic micro- and nanoplastics to elucidate underlying mechanisms. We prepared Realistic nano-polystyrene microplastics (Realistic-NPs) via mechanical fragmentation to mimic environmental plastics debris, characterized by irregular morphology and heterogeneous size distribution confirmed by FTIR and SEM analyses. Realistic-NPs exposure induced depressive-like behaviors in mice as early as 2 weeks, following spatial learning and memory deficits observed at 4 and 8 weeks. Histopathology revealed significant neuronal damage predominantly in prefrontal cortex, despite Realistic-NPs accumulated equally in prefrontal cortex and hippocampus. Mechanistically, Realistic-NPs triggered ferroptosis in above two brain regions, however, more pronounced iron overload, lipid peroxidation, and dysregulated ferroptosis markers were showed in prefrontal cortex. Treatment with the iron chelator deferoxamine mitigated these neurobehavioral and biochemical abnormalities. Realistic-NPs exposure induced mitochondrial iron overload in HT22 cells, which was mediated by upregulation of the mitochondrial iron importer MFRN2, and consequently contributed to mitochondrial dysfunction and ferroptosis. Integrative Mendelian randomization and single-cell transcriptomic data mining identified nuclear receptor coactivator 4 (NCOA4) as a central regulator linking ferroptosis to micro- and nanoplastics induced depressive-like behavior. Pharmacological inhibition of autophagy reduced ferroptosis induced by Realistic-NPs and improved neuronal survival. Collectively, our findings demonstrate that Realistic-NPs induce neurotoxicity through NCOA4-dependent ferritinophagy and ferroptosis mediated by mitochondrial iron overload, highlighting novel targets for therapeutic intervention against microplastic-induced neurological impairments.