Abstract: This study explored the efficacy and mechanism of 10-hydroxy-2-decenoic acid (10-HDA) in alleviating imidacloprid (IMI)-induced liver injury using network pharmacology, network toxicology, and zebrafish models. First, the toxicity of IMI was predicted using the ADMET database, and potential targets associated with 10-HDA, IMI, and liver injury were predicted using the Swiss, DisGenet, and GeneCards databases. The intersection targets were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking was performed to investigate the interactions between 10-HDA and intersection targets. Subsequently, the predictions were validated in zebrafish models, where the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), antioxidant enzymes, and the mRNA expression levels of inflammatory cytokines were measured. Network pharmacology and toxicology analyses indicated that IMI had hepatotoxicity, while 10-HDA exerted a hepatoprotective effect through regulating 82 GO terms and 16 signaling pathways. Furthermore, animal experiments confirmed that IMI induced liver injury through triggering oxidative stress and inflammatory response, and that 10-HDA stabilized the antioxidant defense system by maintaining the activity of antioxidant enzymes in zebrafish. Additionally, 10-HDA reduced inflammation by up-regulating the mRNA expression of anti-inflammatory cytokines (il4 and il10) and down-regulating the expression of pro-inflammatory cytokines (il1β, tnfα, nfκb, and tlr4). In conclusion, 10-HDA alleviates IMI-induced liver injury by attenuating oxidative stress and inflammatory response.

Key words: network pharmacology; network toxicology; liver injury; 10-hydroxy-2-decenoic acid; imidacloprid; zebrafish