Taxifolin Attenuates Doxorubicin-Induced Heart, Liver, and Kidney Toxicity in Mice via Targeting TLR4

Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent widely used for treating lymphoma, leukemia, and sarcoma, but its clinical application is severely restricted by dose-dependent cardiotoxicity, hepatotoxicity, and nephrotoxicity. This study aimed to investigate the mechanisms underlying DOX-induced multi-organ toxicity and identify targeted therapeutic natural compounds through an integrated approach combining network toxicology, virtual screening, molecular docking, molecular dynamics simulation, and in vivo validation. Potential targets were obtained by intersecting drug targets from SwissTargetPrediction, SuperPred, PharmMapper, DrugBank, TTD, ChEMBL, PubChem, and DGIdb databases with injury-related targets from GeneCards, OMIM, and TTD databases. Ten protein-protein interaction network analyses were performed to identify core targets, revealing 24 potential targets involved in DOX-induced toxicity. Gene Ontology enrichment analysis identified 1515 biological processes, 44 cellular components, and 90 molecular functions, while KEGG analysis highlighted 107 significant pathways including lipid and atherosclerosis-related signaling. TLR4 was prioritized as the top hub target, and reverse virtual screening of the natural product database identified taxifolin as a high-affinity candidate with favorable ADMET properties. Molecular docking and dynamics simulations confirmed stable taxifolin-TLR4 complex formation. In vivo experiments using a mouse model demonstrated that taxifolin significantly ameliorated serum biomarker elevations and histopathological damage in heart, liver, and kidney tissues while effectively suppressing TLR4 protein expression. These findings establish taxifolin as a promising TLR4-targeted natural therapeutic agent for mitigating DOX-induced multi-organ toxicity.