To verify whether Shenfu Decoction alleviates heart failure by regulating ferroptosis.Methods:Network pharmacology was employed to identify the common genes shared by Shenfu Decoction，heart failure，and ferroptosis.Metascape was used for Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses.Doxorubicin was used to treat H9C2 cells to establish the cell injury model.The cell viability，Fe2+ content，ferroptosis marker，and expression of the Janus kinase 2(JAK2)-signal transducer and activator of transcription 3(STAT3) signaling pathway were measured.C57 mice were injected with doxorubicin for 4 weeks to establish a model of heart failure.The left ventricular ejection fraction and Fe2+ content in the muscle were measured，and the myocardial morphological changes were observed.Immunohistochemistry was employed to examine the expression level of related proteins in the myocardium.Results:A total of 13 genes shared by Shenfu Decoction，heart failure，and ferroptosis were predicted.Prostaglandin-endoperoxide synthase 2(PTGS2) was the core target of Shenfu Decoction in treating heart failure via ferroptosis.The GO functional analysis revealed 11，3，and 3 terms of biological processes，cellular components，and molecular functions，respectively.The KEGG pathway enrichment analysis predicted 4 signaling pathways.JAK-STAT was the main pathway involved in heart failure.Molecular docking showcased that the docking energy was less than -5 kcal/mol for all the docking combinations.The serum containing Shenfu Decoction improved cell viability，reduced Fe2+ content，inhibited ferroptosis marker，and modulated the JAK2-STAT3 signaling pathway.The animal experiment confirmed that Shenfu Decoction repaired the morphological changes of myocardial cells and improved the cardiac function in mice，which supported the results of the cell experiments on ferroptosis and the modulation mechanism involving the JAK2-STAT3 signaling pathway.Conclusion:This study confirmed that Shenfu Decoction treated heart failure by regulating ferroptosis，enriching the scientific evidence of Shenfu Decoction in regulating myocardial cell death.