Ferroptosis and hepatic fibrosis induced by cooperative exposure to polylactic acid nanoplastics and copper: Emphasis on gut microbiota dysbiosis

Co-exposure to polylactic acid nanoplastics (PLA-NPs) and copper (Cu) in the environment poses a health risk, yet their combined toxic effects remain poorly understood. This study investigated the synergistic hepatotoxicity and underlying mechanisms, focusing on the gut-liver axis, in a mouse model of subacute exposure. Results demonstrated that co-exposure caused significant synergistic effects, including exacerbated changes in body weight (BW), increased hepatic index ratio, and severe liver injury marked by elevated Aspartate Aminotransferase/Alanine Aminotransferase/Alkaline Phosphatase (AST/ALT/AKP) activities and histopathological damage. Crucially, co-exposure synergistically induced hepatic ferroptosis (evidenced by dysregulated Glutathione (GSH), Malondialdehyde (MDA), and iron homeostasis), disrupted lipid metabolism, and promoted oxidative stress. These hepatic injuries were indeced by intestinal barrier damage and gut microbiota dysbiosis, characterized by reduced beneficial Lactobacillus murinus. The fecal microbiota transplantation (FMT) experiment definitively confirmed the causal role of gut microbiota, as transferring microbiota from donor mice to healthy recipients recapitulated the key hepatointestinal injuries. This study demonstrates that co-exposure to PLA-NPs and Cu induces synergistic hepatotoxicity primarily mediated through gut microbiota disruption and gut-liver axis dysfunction, leading to hepatic ferroptosis and fibrosis. These findings highlight the critical role of the gut microbiome in modulating the synergistic toxicity of environmental contaminants and provide new insights into the health risks of mixed pollutant exposure.