Exposure to polystyrene microplastics exacerbates hippocampal inflammation and ferroptosis in mice following chronic sleep deprivation.

Chronic sleep deprivation (CSD) is closely associated with impairments in learning and memory, neuroinflammation, and ferroptosis, potentially increasing vulnerability to harmful environmental exposures. Polystyrene microplastics (PS-MPs) can induce oxidative stress and inflammation, yet their impact on hippocampal pathology and cognition under CSD remains unclear. Here, we established a mouse model combining oral PS-MPs exposure with CSD and assessed cognition using the novel object recognition (NOR) test, open-field test (OFT), Y-maze, and nest-building. CSD markedly promoted PS-MPs deposition in the hippocampus, and PS-MPs further aggravated CSD-induced cognitive deficits, accompanied by more severe neuronal structural damage and loss. PS-MPs also amplified CSD-induced neuroinflammation, increasing IL-6 and TNF-α, decreasing IL-4 and IL-10, and enhancing microglial activation. In BV2 cells, PS-MPs induced dose-dependent inflammatory responses with SOCS3 downregulation and increased p-STAT3. In addition, PS-MPs further elevated hippocampal ROS, MDA, and Fe²⁺ levels, reduced GSH, and aggravated mitochondrial shrinkage and membrane densification. In BV2 cells, PS-MPs also induced ferroptosis in a dose-dependent manner and suppressed SLC7A11/GPX4 expression. In summary, under CSD conditions, PS-MPs accumulate in the hippocampus and promote microglia-mediated neuroinflammation and ferroptosis through SOCS3/STAT3 and SLC7A11/GPX4 signaling, thereby worsening hippocampal injury and cognitive decline.