Polystyrene nanoplastics induce hippocampal damage and cognitive deficits through oxidative stress-triggered microglial extracellular traps and neuronal ferroptosis

Exposure to polystyrene nanoplastics (PS-NPs) induces cognitive deficits and hippocampal damage in mice; however, the underlying mechanism remains unclear. The behavioral assessments performed in this study revealed significant impairments in learning and spatial memory in mice exposed to PS-NPs. Mechanistically, PS-NPs triggered oxidative stress in the hippocampus, which activated microglia and drove the excessive formation and release of microglial extracellular traps (MiETs). This sustained neuroinflammatory response, characterized by the release of MiETs and increased levels of proinflammatory cytokines (Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β)), was closely associated with neuronal Ferroptosis. Ultimately, PS-NPs induced hippocampal Ferroptosis, as evidenced by the loss of mitochondrial cristae, depletion of glutathione (GSH) and Glutathione Peroxidase 4 (GPX4), elevated lipid peroxidation, and disrupted iron homeostasis, characterized by reduced ferritin heavy chain 1 (FTH1) expression and increased levels of ferrous iron. Notably, the antioxidant N-acetylcysteine (NAC) effectively attenuated oxidative stress, suppressed microglial activation and MiET formation, and reduced neuroinflammation, thereby preventing neuronal Ferroptosis and cognitive impairment. Coculture experiments confirmed that PS-NPs-induced MiETs mediate neuronal Ferroptosis, and inhibition of Ferroptosis ameliorates PS-NPs-driven neuroinflammation. These results demonstrate that PS-NPs induce cognitive impairment primarily through an oxidative stress-driven cascade involving microglial activation, MiET release, neuroinflammation, and hippocampal Ferroptosis.