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Mechanisms of Bellidifolin in Treating Doxorubicin-Induced Cardiotoxicity: Network Pharmacology, Molecular Docking,

Xinmeng Zhao^1,2,3, Zhenyang Zhong^1,2,3, Fan Gao³

¹Department of Biochemistry and Molecular Biology, College of Pharmacy, Hebei University of Chinese Medicine, 050200 Shijiazhuang, Hebei, China.

Frontiers in Bioscience (Landmark Edition)

|January 29, 2026

Abstract

Background:

This study aims to examine the roles and mechanisms of action of bellidifolin (BEL) in alleviating doxorubicin-mediated cardiotoxicity using network pharmacology and experimental validation .

Materials And Methods:

Mice with doxorubicin-induced cardiotoxicity were randomly assigned to control, model, BEL, and dexrazoxane (DEX) groups. Echocardiography, histological staining, network pharmacology, and molecular validation were employed to assess cardiac function and myocardial injury. Immunohistochemical staining, western blotting, and RT-qPCR were used to confirm predicted targets and fibrosis biomarkers.

Results:

In vivo experiments demonstrated that BEL significantly improved cardiac function, as indicated by enhanced Ejection Fraction (EF) and Fractional Shortening (FS) compared to the model group (p < 0.01). BEL also notably reduced myocardial injury markers, including creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH) (p < 0.01), and alleviated doxorubicin-induced myocardial fibrosis. Network pharmacology identified 61 common target genes for BEL and cardiotoxicity. Proteinprotein interaction (PPI) network analysis highlighted 16 core genes, including transforming growth factor (TGF)-β1. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that BEL's action pathways were primarily linked to the PI3K-AKT signaling pathway. Molecular docking and dynamic simulations showed a strong binding affinity between BEL and the core target TGF-β1. In vivo validation confirmed that BEL significantly downregulated the expression of TGF-β1, α-smooth muscle actin (SMA), collagen I (Col I), and collagen III (Col III) in myocardial tissue (p < 0.01 or p < 0.05), while activating the PI3K-AKT signaling pathway (p < 0.01 or p < 0.05).

Conclusion:

BEL presents as a promising therapeutic candidate for cardiotoxicity, likely through its anti-fibrotic effects via the reduction of TGF-β1, α-SMA, Col I, and Col III expression, alongside regulation in the PI3K-AKT signaling pathway.

Keywords:

cardiotoxicity doxorubicin endomyocardial fibrosis molecular dynamics simulation network pharmacology

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