Coexposure to heat stress and polystyrene nanoplastics induces neuroinflammation and cognitive impairment via oxidative stress-NLRP6-pyroptosis axis

Global warming and plastic pollution constitute interconnected environmental threats. However, their combined neurotoxic effects, particularly in the context of climate change-driven temperature rise, remain unexplored, posing a critical knowledge gap for environmental health risk assessment. To address this gap, we developed a mouse model subjected to coexposure to heat stress (36 °C, 4 h/day) and well-characterized polystyrene nanoplastics (PS-NPs, 60 nm, 10 mg/kg/day) for 30 consecutive days. Multidisciplinary approaches, including behavioral testing, histopathological analysis and molecular profiling, were employed to assess cognitive dysfunction and its underlying mechanisms. Compared with the single-exposure groups, coexposure induced pronounced cognitive deficits in mice, which were concomitant with hippocampal neurodegeneration, bloodbrain barrier (BBB) compromise, and exacerbated hippocampal oxidative stress. Transcriptomic profiling and subsequent validation revealed a novel role for oxidative stress-induced NLR family pyrin domain containing 6 (NLRP6) inflammasome activation in driving microglial pyroptosis, which exacerbates neuroinflammation through a feedforward loop. The administration of the antioxidant N-acetylcysteine (NAC) attenuated these pathological alterations by suppressing oxidative damage, thereby rescuing cognitive performance. This study elucidates a novel mechanism whereby heat stress and PS-NP coexposure synergistically disrupt neurological homeostasis via redox-sensitive inflammatory pathways, offering critical insights for the development of preventive strategies against combined environmental neurotoxicity.