Polystyrene nanoplastics exposure trigger cognitive impairment mitigated by luteolin modulated glucose-6-phosphate dehydrogenase/glutathione-dependent pathway

The neurotoxicological consequences of chronic exposure to polystyrene nanoplastics (PSNPs) at environmentally relevant concentrations remain poorly understood, particularly their impact on hippocampal neurons dysfunction. In this study, a mouse model co-exposed to PSNPs and/or luteolin (LUT) was replicated by intraperitoneal injection to investigate the mechanism and effective treatment of PSNPs induced striatal neurodegeneration. Here, we elucidated that PSNPs exposure induced striatal injury characterized by neuronal disorganization and mitochondrial dysfunction in vivo and in vitro. Notably, PSNPs triggered oxidative dysregulation and iron accumulation by enhancing antioxidant enzyme activity and suppressing lipid peroxidation, leading to ferroptosis and neuroinflammation. Additionally, PSNPs exposure induced a decrease in glycolysis and tricarboxylic acid (TCA) cycle imbalance by disrupting G6PD/glutathione-dependent pathway, leading to an imbalance in cellular energy metabolism. Our findings highlighted the role of the Piezo1/CaN/NFAT1 axis in PSNPs-induced ER Ca^2 + homeostasis imbalance, which was effectively inhibited by LUT. Notably, LUT alleviated the susceptibility to striatal ferroptosis induced by PSNPs via the G6PD/glutathione axis. Collectively, our study provides critical insights into the neurotoxic mechanisms of PSNPs and establishes LUT as a agent against PSNPs-induced neurodegeneration. These findings underscore the urgent need for environmental regulation of nanoplastics and offer potential strategies for combating their health effects.