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2000
Volume 21, Issue 3
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Background

The clinical use of doxorubicin (DOX), an anthracycline antibiotic with broad-spectrum applications against various malignant tumors, is limited by doxorubicin-induced cardiotoxicity (DIC). Eriodictyol (ERD) has shown cardioprotective effects, but the mechanism of its protective effect on DIC remains unknown.

Aims

This study aimed to explore the potential mechanisms by which ERD confers protection against DIC.

Methods

ERD and DIC targets were identified from the TCMSP, PharmMaper, SwissTargetPrediction, TargetNet, BATMAN, GeneCards, and PharmGKB databases. Differential gene expression data between DIC and normal tissues were extracted from the GEO database. A protein‒protein interaction (PPI) network of the intersecting ERD-DIC targets was constructed using the STRING platform and visualized with Cytoscape 3.10.0 software. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for ERD-DIC cross-targets were conducted. Validation included molecular docking with AutoDock Tools software and molecular dynamics simulations with Gromacs 2019.6 software.

Results

Network pharmacology analysis revealed 43 intersecting ERD-DIC targets, including 6 key targets. GO functional enrichment analysis indicated that the intersecting targets were enriched in 550 biological processes, 45 cell components, and 41 molecular functions. KEGG pathway enrichment analysis identified 114 enriched signaling pathways. Molecular docking revealed a strong binding affinity between ERD and 6 key targets, as well as multiple targets within the ROS pathway. Molecular dynamics simulations indicated that ERD has favorable binding with 3 crucial targets.

Conclusion

The systematic network pharmacology analysis suggests that ERD may mitigate DIC through multiple targets and pathways, with the ROS pathway potentially playing a crucial role. These findings provide a reference for foundational research and clinical applications of ERD in treating DIC.

© 2025 Bentham Science Publishers
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2025-11-07

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References

  1. SingalP.K. IliskovicN. Doxorubicin-induced cardiomyopathy.N. Engl. J. Med.19983391390090510.1056/NEJM199809243391307 9744975
     [Google Scholar]
  2. SwainS.M. WhaleyF.S. EwerM.S. Congestive heart failure in patients treated with doxorubicin.Cancer200397112869287910.1002/cncr.11407 12767102
     [Google Scholar]
  3. LefrakE.A. PiťhaJ. RosenheimS. GottliebJ.A. A clinicopathologic analysis of adriamycin cardiotoxicity.Cancer197332230231410.1002/1097‑0142(197308)32:2<302:AID‑CNCR2820320205>3.0.CO;2‑2 4353012
     [Google Scholar]
  4. IchikawaY. GhanefarM. BayevaM. WuR. KhechaduriA. PrasadS.V.N. MutharasanR.K. NaikT.J. ArdehaliH. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.J. Clin. Invest.2014124261763010.1172/JCI72931 24382354
     [Google Scholar]
  5. SpetzJ. MoslehiJ. SarosiekK. Radiation-induced cardiovascular toxicity: Mechanisms, prevention, and treatment.Curr. Treat. Options Cardiovasc. Med.20182043110.1007/s11936‑018‑0627‑x 29556748
     [Google Scholar]
  6. GodishalaA. YangS. AsnaniA. Cardioprotection in the modern era of cancer chemotherapy.Cardiol. Rev.201826311312110.1097/CRD.0000000000000194 29608498
     [Google Scholar]
  7. GammellaE. MaccarinelliF. BurattiP. RecalcatiS. CairoG. The role of iron in anthracycline cardiotoxicity.Front. Pharmacol.201452510.3389/fphar.2014.00025 24616701
     [Google Scholar]
  8. NabhanC. ByrtekM. RaiA. DawsonK. ZhouX. LinkB.K. FriedbergJ.W. ZelenetzA.D. MaurerM.J. CerhanJ.R. FlowersC.R. Disease characteristics, treatment patterns, prognosis, outcomes and lymphoma‐related mortality in elderly follicular lymphoma in the United States.Br. J. Haematol.20151701859510.1111/bjh.13399 25851937
     [Google Scholar]
  9. Abdel-DaimM.M. kilany, O.E.; Khalifa, H.A.; Ahmed, A.A.M. Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via. suppression of oxidative stress, inflammation and apoptosis.Cancer Chemother. Pharmacol.201780474575310.1007/s00280‑017‑3413‑7 28785995
     [Google Scholar]
  10. OctaviaY. TocchettiC.G. GabrielsonK.L. JanssensS. CrijnsH.J. MoensA.L. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies.J. Mol. Cell. Cardiol.20125261213122510.1016/j.yjmcc.2012.03.006 22465037
     [Google Scholar]
  11. LiD.L. WangZ.V. DingG. TanW. LuoX. CriolloA. XieM. JiangN. MayH. KyrychenkoV. SchneiderJ.W. GilletteT.G. HillJ.A. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification.Circulation2016133171668168710.1161/CIRCULATIONAHA.115.017443 26984939
     [Google Scholar]
  12. VejpongsaP. YehE.T.H. Prevention of anthracycline-induced cardiotoxicity: Challenges and opportunities.J. Am. Coll. Cardiol.201464993894510.1016/j.jacc.2014.06.1167 25169180
     [Google Scholar]
  13. LiD. LiuX. PiW. ZhangY. YuL. XuC. SunZ. JiangJ. Fisetin attenuates doxorubicin-induced cardiomyopathy in vivo and in vitro by inhibiting ferroptosis through SIRT1/Nrf2 signaling pathway activation.Front. Pharmacol.20221280848010.3389/fphar.2021.808480 35273493
     [Google Scholar]
  14. ChenH. ZhuJ. LeY. PanJ. LiuY. LiuZ. WangC. DouX. LuD. Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway.Phytomedicine20229915396410.1016/j.phymed.2022.153964 35180677
     [Google Scholar]
  15. HeH. WangL. QiaoY. YangB. YinD. HeM. Epigallocatechin-3-gallate pretreatment alleviates doxorubicin-induced ferroptosis and cardiotoxicity by upregulating AMPKα2 and activating adaptive autophagy.Redox Biol.20214810218510.1016/j.redox.2021.102185 34775319
     [Google Scholar]
  16. IslamA. IslamM.S. RahmanM.K. UddinM.N. AkandaM.R. The pharmacological and biological roles of eriodictyol.Arch. Pharm. Res.202043658259210.1007/s12272‑020‑01243‑0 32594426
     [Google Scholar]
  17. LiL. LiW.J. ZhengX.R. LiuQ.L. DuQ. LaiY.J. LiuS.Q. Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation.Mol. Med.20222811110.1186/s10020‑022‑00442‑3 35093024
     [Google Scholar]
  18. LvF. DuQ. LiL. XiX. LiuQ. LiW. LiuS. Eriodictyol inhibits glioblastoma migration and invasion by reversing EMT via downregulation of the P38 MAPK/GSK-3β/ZEB1 pathway.Eur. J. Pharmacol.202190017406910.1016/j.ejphar.2021.174069 33811837
     [Google Scholar]
  19. LiD. LuN. HanJ. ChenX. HaoW. XuW. LiuX. YeL. ZhengQ. Eriodictyol attenuates myocardial ischemia-reperfusion injury through the activation of JAK2.Front. Pharmacol.201893310.3389/fphar.2018.00033 29441020
     [Google Scholar]
  20. XieY. JiR. HanM. Eriodictyol protects H9c2 cardiomyocytes against the injury induced by hypoxia/reoxygenation by improving the dysfunction of mitochondria.Exp. Ther. Med.2019171551557 30651835
     [Google Scholar]
  21. RuJ. LiP. WangJ. ZhouW. LiB. HuangC. LiP. GuoZ. TaoW. YangY. XuX. LiY. WangY. YangL. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines.J. Cheminform.2014611310.1186/1758‑2946‑6‑13 24735618
     [Google Scholar]
  22. WangX. ShenY. WangS. LiS. ZhangW. LiuX. LaiL. PeiJ. LiH. PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database.Nucleic Acids Res.201745W1W356W36010.1093/nar/gkx374 28472422
     [Google Scholar]
  23. DainaA. MichielinO. ZoeteV. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules.Nucleic Acids Res.201947W1W357W36410.1093/nar/gkz382 31106366
     [Google Scholar]
  24. YaoZ.J. DongJ. CheY.J. ZhuM.F. WenM. WangN.N. WangS. LuA.P. CaoD.S. TargetNet: A web service for predicting potential drug–target interaction profiling via multi-target SAR models.J. Comput. Aided Mol. Des.201630541342410.1007/s10822‑016‑9915‑2 27167132
     [Google Scholar]
  25. KongX. LiuC. ZhangZ. ChengM. MeiZ. LiX. BATMAN-TCM 2.0: An enhanced integrative database for known and predicted interactions between traditional Chinese medicine ingredients and target proteins.Nucleic Acids Res.2023 37904598
     [Google Scholar]
  26. Whirl-CarrilloM. HuddartR. GongL. SangkuhlK. ThornC.F. WhaleyR. KleinT.E. An evidence‐based framework for evaluating pharmacogenomics knowledge for personalized medicine.Clin. Pharmacol. Ther.2021110356357210.1002/cpt.2350 34216021
     [Google Scholar]
  27. StelzerG RosenN PlaschkesI ZimmermanS TwikM FishilevichS The GeneCards Suite: From gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics20165411.301-1.30.33.
     [Google Scholar]
  28. BarrettT. WilhiteS.E. LedouxP. EvangelistaC. KimI.F. TomashevskyM. MarshallK.A. PhillippyK.H. ShermanP.M. HolkoM. YefanovA. LeeH. ZhangN. RobertsonC.L. SerovaN. DavisS. SobolevaA. NCBI GEO: Archive for functional genomics data sets--update.Nucleic Acids Res.201341Database issueD991D995 23193258
     [Google Scholar]
  29. SzklarczykD. FranceschiniA. WyderS. ForslundK. HellerD. Huerta-CepasJ. SimonovicM. RothA. SantosA. TsafouK.P. KuhnM. BorkP. JensenL.J. von MeringC. STRING v10: Protein–protein interaction networks, integrated over the tree of life.Nucleic Acids Res.201543D1D447D45210.1093/nar/gku1003 25352553
     [Google Scholar]
  30. ShannonP. MarkielA. OzierO. BaligaN.S. WangJ.T. RamageD. AminN. SchwikowskiB. IdekerT. Cytoscape: A software environment for integrated models of biomolecular interaction networks.Genome Res.200313112498250410.1101/gr.1239303 14597658
     [Google Scholar]
  31. MiH. MuruganujanA. HuangX. EbertD. MillsC. GuoX. ThomasP.D. Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0).Nat. Protoc.201914370372110.1038/s41596‑019‑0128‑8 30804569
     [Google Scholar]
  32. ZhouY. ZhouB. PacheL. ChangM. KhodabakhshiA.H. TanaseichukO. BennerC. ChandaS.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.Nat. Commun.2019101152310.1038/s41467‑019‑09234‑6 30944313
     [Google Scholar]
  33. BermanH.M. WestbrookJ. FengZ. GillilandG. BhatT.N. WeissigH. ShindyalovI.N. BourneP.E. The protein data bank.Nucleic Acids Res.200028123524210.1093/nar/28.1.235 10592235
     [Google Scholar]
  34. KimS. ChenJ. ChengT. GindulyteA. HeJ. HeS. LiQ. ShoemakerB.A. ThiessenP.A. YuB. ZaslavskyL. ZhangJ. BoltonE.E. PubChem 2023 update.Nucleic Acids Res.202351D1D1373D138010.1093/nar/gkac956 36305812
     [Google Scholar]
  35. WallaceA.C. LaskowskiR.A. ThorntonJ.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions.Protein Eng. Des. Sel.19958212713410.1093/protein/8.2.127 7630882
     [Google Scholar]
  36. ZhangY.C. GaoW.C. ChenW.J. PangD.X. MoD.Y. YangM. Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Fei Jin Sheng Formula in the treatment of lung cancer.Curr. Pharm. Des.202329141121113410.2174/1381612829666230503164755 37138492
     [Google Scholar]
  37. Ul HaqF. AbroA. RazaS. LiedlK.R. AzamS.S. Molecular dynamics simulation studies of novel β-lactamase inhibitor.J. Mol. Graph. Model.20177414315210.1016/j.jmgm.2017.03.002 28432959
     [Google Scholar]
  38. ArquesS. Human serum albumin in cardiovascular diseases.Eur. J. Intern. Med.20185281210.1016/j.ejim.2018.04.014 29680174
     [Google Scholar]
  39. De SimoneG. di MasiA. AscenziP. Serum albumin: A multifaced enzyme.Int. J. Mol. Sci.202122181008610.3390/ijms221810086 34576249
     [Google Scholar]
  40. TaipaleM. JaroszD.F. LindquistS. HSP90 at the hub of protein homeostasis: Emerging mechanistic insights.Nat. Rev. Mol. Cell Biol.201011751552810.1038/nrm2918 20531426
     [Google Scholar]
  41. ZhangJ. LiH. LiuY. ZhaoK. WeiS. SugarmanE.T. LiuL. ZhangG. Targeting HSP90 as a novel therapy for cancer: Mechanistic insights and translational relevance.Cells20221118277810.3390/cells11182778 36139353
     [Google Scholar]
  42. GarcíaR. MerinoD. GómezJ.M. NistalJ.F. HurléM.A. CortajarenaA.L. VillarA.V. Extracellular heat shock protein 90 binding to TGFβ receptor I participates in TGFβ-mediated collagen production in myocardial fibroblasts.Cell. Signal.201628101563157910.1016/j.cellsig.2016.07.003 27418101
     [Google Scholar]
  43. WenS.Y. AliA. HuangI.C. LiuJ.S. ChenP.Y. Padma ViswanadhaV. HuangC.Y. KuoW.W. Doxorubicin induced ROS-dependent HIF1α activation mediates blockage of IGF1R survival signaling by IGFBP3 promotes cardiac apoptosis.Aging (Albany NY)202315116417810.18632/aging.204466 36602546
     [Google Scholar]
  44. HolbroT. HynesN.E. ErbB receptors: Directing key signaling networks throughout life.Annu. Rev. Pharmacol. Toxicol.200444119521710.1146/annurev.pharmtox.44.101802.121440 14744244
     [Google Scholar]
  45. HerventA.S. De KeulenaerG.W. Molecular mechanisms of cardiotoxicity induced by ErbB receptor inhibitor cancer therapeutics.Int. J. Mol. Sci.20121312122681228610.3390/ijms131012268 23202898
     [Google Scholar]
  46. ChitturiK.R. BurnsE.A. MuhsenI.N. AnandK. TrachtenbergB.H. Cardiovascular risks with Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors and monoclonal antibody therapy.Curr. Oncol. Rep.202224447549110.1007/s11912‑022‑01215‑1 35192115
     [Google Scholar]
  47. AlhoshaniA. AlanaziF.E. AlotaibiM.R. AttwaM.W. KadiA.A. AldhfyanA. AkhtarS. HouraniS. AgouniA. ZeidanA. KorashyH.M. EGFR inhibitor gefitinib induces cardiotoxicity through the modulation of cardiac PTEN/Akt/FoxO3a pathway and reactive metabolites formation: In vivo and in vitro rat studies.Chem. Res. Toxicol.20203371719172810.1021/acs.chemrestox.0c00005 32370496
     [Google Scholar]
  48. NormannoN. De LucaA. BiancoC. StrizziL. MancinoM. MaielloM.R. CarotenutoA. De FeoG. CaponigroF. SalomonD.S. Epidermal growth factor receptor (EGFR) signaling in cancer.Gene2006366121610.1016/j.gene.2005.10.018 16377102
     [Google Scholar]
  49. AnandK. EnsorJ. TrachtenbergB. BernickerE.H. Osimertinib-induced cardiotoxicity.JACC Cardiooncol.20191217217810.1016/j.jaccao.2019.10.006 34396179
     [Google Scholar]
  50. HevenerA.L. RibasV. MooreT.M. ZhouZ. ERα in the control of mitochondrial function and metabolic health.Trends Mol. Med.2021271314610.1016/j.molmed.2020.09.006 33020031
     [Google Scholar]
  51. Puzianowska-KuźnickaM. ESR1 in myocardial infarction.Clin. Chim. Acta20124131-2818710.1016/j.cca.2011.10.028 22061094
     [Google Scholar]
  52. WangM. CrisostomoP. WairiukoG.M. MeldrumD.R. Estrogen receptor-α mediates acute myocardial protection in females.Am. J. Physiol. Heart Circ. Physiol.20062906H2204H220910.1152/ajpheart.01219.2005 16415070
     [Google Scholar]
  53. DucharmeA. FrantzS. AikawaM. RabkinE. LindseyM. RohdeL.E. SchoenF.J. KellyR.A. WerbZ. LibbyP. LeeR.T. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction.J. Clin. Invest.20001061556210.1172/JCI8768 10880048
     [Google Scholar]
  54. SinglaD.K. Akt—mTOR pathway inhibits apoptosis and fibrosis in doxorubicin-induced cardiotoxicity following embryonic stem cell transplantation.Cell Transplant.20152461031104210.3727/096368914X679200 24594448
     [Google Scholar]
  55. GalloS. SpilingaM. AlbanoR. FerrautoG. Di GregorioE. CasanovaE. BalmativolaD. BonzanoA. BoccaccioC. SapinoA. ComoglioP.M. CrepaldiT. Activation of the MET receptor attenuates doxorubicin‐induced cardiotoxicity in vivo and in vitro.Br. J. Pharmacol.2020177133107312210.1111/bph.15039 32133617
     [Google Scholar]
  56. SahuB.D. KumarJ.M. KunchaM. BorkarR.M. SrinivasR. SistlaR. Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice.Life Sci.201614481810.1016/j.lfs.2015.11.018 26606860
     [Google Scholar]
  57. SongboM. LangH. XinyongC. BinX. PingZ. LiangS. Oxidative stress injury in doxorubicin-induced cardiotoxicity.Toxicol. Lett.2019307414810.1016/j.toxlet.2019.02.013 30817977
     [Google Scholar]
  58. MaJ. WangY. ZhengD. WeiM. XuH. PengT. Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways.Cardiovasc. Res.2013971778710.1093/cvr/cvs309 23027656
     [Google Scholar]
  59. ShangP. LiuY. RenJ. LiuQ. SongH. JiaJ. LiuQ. Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1.Open Med. (Wars.)20241912024094310.1515/med‑2024‑0943 38584839
     [Google Scholar]
  60. Koczurkiewicz-AdamczykP. GąsiorkiewiczB. PiskaK. Gunia-KrzyżakA. JamrozikM. BuckiA. SłoczyńskaK. BojdoP. Wójcik-PszczołaK. WładykaB. KołaczkowskiM. PękalaE. Cinnamamide derivatives with 4-hydroxypiperidine moiety enhance effect of doxorubicin to cancer cells and protect cardiomyocytes against drug-induced toxicity through CBR1 inhibition mechanism.Life Sci.202230512077710.1016/j.lfs.2022.120777 35792180
     [Google Scholar]
  61. LiangD. ZhongP. HuJ. LinF. QianY. XuZ. WangJ. ZengC. LiX. LiangG. EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model.J. Mol. Cell. Cardiol.201582637410.1016/j.yjmcc.2015.02.029 25758431
     [Google Scholar]
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Potential Mechanism by which Eriodictyol Protects against Doxorubicin-induced Cardiotoxicity based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation
Curr. Computeraided Drug Des. 21, 316 (2025); https://doi.org/10.2174/0115734099297600240523105601
/content/journals/cad/10.2174/0115734099297600240523105601
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  • Article Type:     Research Article
Keyword(s): cardiotoxicity; doxorubicin; Eriodictyol; molecular docking; network pharmacology; reactive oxygen species

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