Inulin-modified nano selenium biocomposite with dual-targeting capability mitigates polystyrene nanoplastic-induced hepatic ferroptosis

The mutually benefiting relationship between the environment and human health is under threat from the rapid accumulation and trophic transfer of fragmented plastics. While the in vivo presence and adverse effects of nanoplastics in the environment have been increasingly documented in recent years, mainly from the perspectives of toxicology and human health, how to actively mitigate such adverse effects remains an uncharted area of research. In this study, we aimed to fill this gap by employing inulin-modified nano selenium (nano-Se@IN) to counteract polystyrene (PS) nanoplastics-induced hepatic damage, and to elucidate the underlying mechanisms from the perspectives of the gut microbiota, metabolites, metabolism pathways, and hepatic gene expression. Through multi-omics analyses and validation experiments, we demonstrated that nano-Se@IN reversed ferrotinophagy and ferroptosis in mouse hepatocytes by dual pathways. First, nano-Se@IN directly upregulated the GPX4 gene expression in mice liver, boosting GSH biosynthesis and strengthening the GSH-dependent antioxidant defense system. Second, nano-Se@IN restored gut microbiota homeostasis and corrected the gut microbiota-mediated arachidonic acid (AA) metabolism disorder, leading to a marked reduction in circulating pro-ferroptotic AA metabolites. This reduced the hepatic pool of lipid peroxidation substrates required for ferroptosis execution, ultimately alleviating ferroptosis-related liver injury. Our findings established the understanding that nano-Se@IN supplementation represents a promising intervention strategy to mitigate the hepatic toxicity of environmental nanoplastics. This work advances our understanding of nanoplastic toxicology and provides a facile strategy for biological detoxification against nanoplastics.