Dietary Polystyrene Nanoplastics Exacerbate Valproate-Induced Hepatotoxicity via the Gut–Liver Axis, Involving Microbiota Dysbiosis and Metabolic Disorders

Abstract Nanoplastics (NPs) originating from plastic waste can enter crops and aquatic organisms, reaching the human body through dietary intake. This study investigated whether polystyrene nanoplastics (PS-NPs) exacerbate valproate (VPA)-induced chemical liver injury via the gut–liver axis. Mice were exposed to VPA alone or in combination with PS-NPs for four consecutive weeks. Histopathological evaluation revealed more severe liver injury in the coexposure group compared to the VPA-alone group. Mechanistically, PS-NPs disrupted the gut microbiota and hepatic metabolic profiles, activated the NF-κB pathway, and inhibited the Nrf2 signaling pathway, collectively promoting inflammation, oxidative stress, and metabolic disorders. Intervention with mangiferin (MGF) alleviated these pathological changes. These findings suggest that PS-NPs, as emerging agricultural pollutants, aggravate chemical liver injury through an indirect mechanism mediated by the gut–liver axis.