Exploring the mechanism of Taohong Siwu decoction in the treatment of hyperlipidemia based on network pharmacology and zebrafish models

• The active ingredients of TSD are stigmasterol, myricanone, and β-sitosterol etc. • Stigmasterol, myricanone, and β-sitosterol mainly bind to PTGS2 and PIK3CG. • TSD has anti-hyperlipidemic and anti-inflammatory action in HCFD-fed zebrafish. Taohong Siwu Decoction (TSD) is a traditional Chinese medicine used to treat cardiovascular diseases and blood stasis. This study explores the therapeutic mechanisms of TSD in treating hyperlipidemia using a network pharmacology approach combined with a zebrafish hyperlipidemia model. Compounds in TSD were sourced from a database and filtered based on oral bioavailability and drug-likeness. Herbal targets were predicted using online tools, and hyperlipidemia-related genes were identified via GeneCards. Pathway analysis was conducted to pinpoint relevant signaling pathways. Molecular docking, performed with AutoDock, assessed the binding affinity of key compounds to target proteins. In vivo experiments using zebrafish models evaluated the anti-hyperlipidemic, anti-inflammatory, and antioxidant effects of TSD, with RT-qPCR used to verify the expression of predicted targets. Network pharmacology analysis revealed 45 bioactive phytochemicals and 72 potential target genes implicated in hyperlipidemia-related pathways. Six principal bioactive compounds—quercetin, luteolin, myricanone, stigmasterol, kaempferol, and β-sitosterol—were identified as modulators of core therapeutic targets including TNF, IL6, IL1B, PTGS2, PPARG, ESR1, PTGS1, and PIK3CG, influencing critical pathways associated with inflammatory responses, oxidative stress modulation, and lipid metabolism regulation. Molecular docking analysis demonstrated robust binding affinities between these compounds and their respective targets, particularly PTGS2 and PIK3CG. Zebrafish experiments substantiated TSD's therapeutic efficacy in ameliorating hyperlipidemia, attenuating inflammation, and mitigating oxidative stress, thereby validating the predicted mechanisms of action. TSD exhibits a characteristic multi-component, multi-target, and multi-pathway therapeutic profile in the management of hyperlipidemia and associated atherosclerotic conditions. These findings support its clinical application and provide a theoretical basis for future research.