Silver nanoparticles induce liver inflammation through ferroptosis in zebrafish.

As the most widely employed artificial nanomaterials, silver nanoparticles (AgNPs) have been implicated in oxidative stress-induced liver injury. Despite these observations, the precise mechanisms underpinning AgNPs-induced hepatotoxicity have yet to be fully elucidated. This study embarked on an intersectional analysis of the GEO dataset (GSE139560), which encompassed murine liver tissues subjected to AgNPs, alongside datasets related to ferroptosis. Through this approach, three pivotal ferroptosis-associated genes (Arrdc3, Txnip, and Egfr) were identified. Further integration with disease model analysis from GSE111407 and GSE183158 unveiled a significant association between AgNPs exposure and alterations in glucose metabolism and insulin signaling pathways, intricately linked with the identified key ferroptosis genes. This correlation fostered the hypothesis that ferroptosis significantly contributed to the hepatotoxicity triggered by AgNPs. Subsequent Gene Set Enrichment Analysis (GSEA) pointed to the activation of ferroptosis-associated pathways, specifically MAPK and PPAR, under AgNPs exposure. Examination of the miRNA-mRNA interaction network revealed co-regulated upstream miRNAs targeting these pivotal genes, establishing a nexus to ferroptosis and heightened liver susceptibility. Experimental validation employing an adult zebrafish model exposed to AgNPs from 90 to 120 dpf demonstrated elevated levels of Fe and MDA in the zebrafish livers, along with conspicuous mitochondrial morphological alterations, thereby reinforcing the notion that AgNPs precipitate liver dysfunction predominantly through the induction of ferroptosis. These insights collectively underscore the role of ferroptosis in mediating the adverse effects of AgNPs on liver glucose metabolism and insulin sensitivity, culminating in liver dysfunction. Overall, these results enhance the understanding of nanomaterial-induced hepatotoxicity and inform strategies to mitigate such health risks.