Taxifolin targets HMGCR, LDLR and APOB to ameliorate hyperlipidemia: insights from systems pharmacology and nanoemulsion-based delivery

Abstract

Hyperlipidemia is a major risk factor for cardiovascular disease, highlighting the need for safer and effective therapeutic options. This study evaluated the anti-hyperlipidemic potential of taxifolin (TXF) and its nanoemulsion formulation (TXF-NE) using integrated computational and experimental approaches. Network pharmacology identified 177 common targets between TXF and hyperlipidemia, with enrichment analyses linking these targets to lipid metabolism, cholesterol regulation, and inflammatory pathways. Protein-protein interaction analysis revealed key lipid-regulating genes, including HMGCR as a major hub target. Molecular docking predicted favorable interactions of TXF with several lipid metabolism related proteins, including HMGCR, LDLR, APOB, APOA1, and ACSM2A. The predicted interactions provide structural hypotheses regarding potential TXF protein associations. In-vivo , TXF significantly improved serum lipid profiles and liver function enzymes. Gene expression and protein analyses exhibited downregulation of HMGCR and APOB along with upregulation of LDLR, indicating suppression of cholesterol synthesis, reduced lipoprotein production, and enhanced LDL clearance. Notably, TXF-NE exhibited high drug content and better therapeutic efficacy relative to free TXF, as reflected by greater improvements in lipid parameters. Overall, these findings demonstrate that TXF alleviates hyperlipidemia through a multi-target mechanism, while nanoemulsion-based delivery enhances its therapeutic potential for managing hyperlipidemia and associated hepatic dysfunction.