Luteolin alleviates lipid accumulation and hepatic injury in zebrafish larvae by modulating arachidonic acid metabolism.

Excessive lipid accumulation contributes to hepatic oxidative stress, apoptosis, and structural injury. In this work, an egg yolk powder-induced zebrafish larval model was used to investigate the protective effects of luteolin and the associated metabolic mechanisms. Whole-body lipid accumulation, hepatic lipid deposition, liver injury, oxidative stress, and apoptosis were evaluated. Transcriptomic and untargeted metabolomic analyses were integrated to identify luteolin-responsive genes, metabolites, and pathways. Luteolin reduced whole-body lipid accumulation and hepatic lipid deposition, suppressed the model-induced upregulation of genes involved in fatty acid, triglyceride, and cholesterol biosynthesis, and alleviated hepatic structural injury. Luteolin also attenuated oxidative stress and apoptosis induced by excessive lipid exposure. Integrated multi-omics analysis identified arachidonic acid metabolism as a major pathway associated with luteolin treatment. Coordinated alterations in leukotriene-related genes and leukotriene E3 provided the strongest evidence for this pathway, whereas changes related to prostaglandin and cytochrome P450 metabolism indicated additional regulatory components. Pharmacological inhibition with SKF-525A further suggests possible involvement of CYP-dependent metabolism. These findings indicate that luteolin alleviates lipid accumulation and hepatic injury in zebrafish larvae, with arachidonic acid metabolism contributing to its protective effects.