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Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology and experimental validation to reveal the effect and mechanism of costunolide in AIH. A total of 73 common targets of costunolide and AIH were obtained from databases. Pathway enrichment analysis indicated that PI3K-AKT pathway was the core pathway of costunolide in AIH. Protein\u2013protein interaction network analysis and molecular docking revealed that SRC and IGF1R might play critical roles. In two murine AIH models, costunolide significantly attenuated liver injury, inflammation, and fibrosis reflected by the liver gross appearance, serum transaminases, necrosis area, spleen index, immune cell infiltration, and collagen deposition. Western blot and immunohistochemistry confirmed that phosphorylated AKT, SRC, and IGF1R were upregulated in AIH models, and costunolide administration could inhibit the phosphorylation of these proteins. In summary, costunolide significantly ameliorates murine AIH. The therapeutic effect might work by suppressing the activation of PI3K-AKT pathway and inhibiting the phosphorylation of SRC and IGF1R. Our research reveals the potent therapeutic effect of costunolide in AIH and the potential role of SRC and IGF1R in AIH for the first time, which may further contribute to the novel drug development for AIH and other autoimmune diseases.<\/jats:p>","DOI":"10.3390\/ph16020316","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T02:56:02Z","timestamp":1676861762000},"page":"316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Therapeutic Effect of Costunolide in Autoimmune Hepatitis: Network Pharmacology and Experimental Validation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3021-2472","authenticated-orcid":false,"given":"Zheng","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangshu","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sirbe, C., Simu, G., Szabo, I., Grama, A., and Pop, T.L. (2021). Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413578"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41423-021-00768-8","article-title":"Autoimmmune hepatitis","volume":"19","author":"Vergani","year":"2022","journal-title":"Cell. Mol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/j.jhep.2020.07.023","article-title":"Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group","volume":"73","author":"Lohse","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev-pathol-020117-043534","article-title":"Cellular and Molecular Mechanisms of Autoimmune Hepatitis","volume":"13","author":"Webb","year":"2018","journal-title":"Annu. Rev. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/ame2.12201","article-title":"Chinese medicine in the treatment of autoimmune hepatitis: Progress and future opportunities","volume":"5","author":"Liu","year":"2022","journal-title":"Anim. Model. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kim, D.Y., and Choi, B.Y. (2019). Costunolide-A Bioactive Sesquiterpene Lactone with Diverse Therapeutic Potential. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20122926"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jep.2009.06.003","article-title":"Antipyretic and anti-inflammatory properties of the ethanolic extract, dichloromethane fraction and costunolide from Magnolia ovata (Magnoliaceae)","volume":"124","author":"Kassuya","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ejphar.2014.02.031","article-title":"Costunolide and Dehydrocostuslactone, two natural sesquiterpene lactones, ameliorate the inflammatory process associated to experimental pleurisy in mice","volume":"730","author":"Butturini","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.cbi.2016.03.003","article-title":"Evaluation of protective effects of costunolide and dehydrocostuslactone on ethanol-induced gastric ulcer in mice based on multi-pathway regulation","volume":"250","author":"Zheng","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.intimp.2018.06.017","article-title":"Costunolide ameliorates lipoteichoic acid-induced acute lung injury via attenuating MAPK signaling pathway","volume":"61","author":"Chen","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106567","DOI":"10.1016\/j.intimp.2020.106567","article-title":"Costunolide improved dextran sulfate sodium-induced acute ulcerative colitis in mice through NF-kappaB, STAT1\/3, and Akt signaling pathways","volume":"84","author":"Xie","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107688","DOI":"10.1016\/j.intimp.2021.107688","article-title":"Costunolide ameliorates colitis via specific inhibition of HIF1alpha\/glycolysis-mediated Th17 differentiation","volume":"97","author":"Lv","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.3389\/fphar.2018.01469","article-title":"Protective Effects of Costunolide Against D-Galactosamine and Lipopolysaccharide-Induced Acute Liver Injury in Mice","volume":"9","author":"Mao","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1002\/ptr.7383","article-title":"Costunolide protects against alcohol-induced liver injury by regulating gut microbiota, oxidative stress and attenuating inflammation in vivo and in vitro","volume":"36","author":"Mao","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/bph.14873","article-title":"Costunolide represses hepatic fibrosis through WW domain-containing protein 2-mediated Notch3 degradation","volume":"177","author":"Ge","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fphar.2019.00123","article-title":"Network Pharmacology Databases for Traditional Chinese Medicine: Review and Assessment","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"953871","DOI":"10.3389\/fphar.2022.953871","article-title":"Integrative network pharmacology and experimental verification to reveal the anti-inflammatory mechanism of ginsenoside Rh4","volume":"13","author":"To","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, C.R., Chen, H.W., Li, Y., Zhou, M.Y., Wong, V.K., Jiang, Z.H., and Zhang, W. (2021). Network Pharmacology Exploration Reveals Anti-Apoptosis as a Common Therapeutic Mechanism for Non-Alcoholic Fatty Liver Disease Treated with Blueberry Leaf Polyphenols. Nutrients, 13.","DOI":"10.3390\/nu13114060"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"956812","DOI":"10.3389\/fphar.2022.956812","article-title":"DPHB, a diarylheptane from Alpinia officinarum Hance, ameliorates insulin resistance: A network pharmacology and in vitro study","volume":"13","author":"Li","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"681391","DOI":"10.3389\/fmed.2021.681391","article-title":"Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation","volume":"8","author":"Xu","year":"2021","journal-title":"Front. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12967-019-02180-3","article-title":"Plasma proteomic analysis of autoimmune hepatitis in an improved AIH mouse model","volume":"18","author":"Wang","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: A database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1111\/jgh.14746","article-title":"Systematic review and meta-analysis on the incidence and prevalence of autoimmune hepatitis in Asian, European, and American population","volume":"34","author":"Lv","year":"2019","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13046-021-01895-w","article-title":"Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo","volume":"40","author":"Huang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.jhep.2020.01.023","article-title":"NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly","volume":"72","author":"He","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"810671","DOI":"10.3389\/fimmu.2022.810671","article-title":"CCN1 Promotes Inflammation by Inducing IL-6 Production via alpha6beta1\/PI3K\/Akt\/NF-kappaB Pathway in Autoimmune Hepatitis","volume":"13","author":"Jiang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/hep.28825","article-title":"Effects of kinsenoside, a potential immunosuppressive drug for autoimmune hepatitis, on dendritic cells\/CD8(+) T cells communication in mice","volume":"64","author":"Xiang","year":"2016","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1055\/s-0036-1597819","article-title":"The Role of Akt in Chronic Liver Disease and Liver Regeneration","volume":"37","author":"Santel","year":"2017","journal-title":"Semin. Liver Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1084\/jem.20071477","article-title":"The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells","volume":"205","author":"Haxhinasto","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/ni.2005","article-title":"The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2","volume":"12","author":"Delgoffe","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.immuni.2021.04.008","article-title":"Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses","volume":"54","author":"Xu","year":"2021","journal-title":"Immunity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1126\/science.abb2683","article-title":"Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity","volume":"371","author":"Xu","year":"2021","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-016-0343-5","article-title":"Targeting of PI3K\/AKT\/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development","volume":"9","author":"Almeida","year":"2016","journal-title":"J. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.jaut.2012.04.001","article-title":"Attenuation of phosphoinositide 3-kinase delta signaling restrains autoimmune disease","volume":"38","author":"Maxwell","year":"2012","journal-title":"J. Autoimmun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nm1284","article-title":"Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis","volume":"11","author":"Camps","year":"2005","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s12943-022-01662-1","article-title":"Costunolide is a dual inhibitor of MEK1 and AKT1\/2 that overcomes osimertinib resistance in lung cancer","volume":"21","author":"Tian","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.3389\/fphar.2019.01189","article-title":"Methylprednisolone Decreases Mitochondria-Mediated Apoptosis and Autophagy Dysfunction in Hepatocytes of Experimental Autoimmune Hepatitis Model via the Akt\/mTOR Signaling","volume":"10","author":"Fan","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jaut.2016.02.007","article-title":"Non-alcoholic fatty liver disease (NAFLD) potentiates autoimmune hepatitis in the CYP2D6 mouse model","volume":"69","author":"Muller","year":"2016","journal-title":"J. Autoimmun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.phrs.2015.01.003","article-title":"Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors","volume":"94","author":"Roskoski","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1007\/s11481-014-9553-1","article-title":"IL-17A induces MIP-1alpha expression in primary astrocytes via Src\/MAPK\/PI3K\/NF-kB pathways: Implications for multiple sclerosis","volume":"9","author":"Yi","year":"2014","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3389\/fbioe.2020.00392","article-title":"Exploring the Role of SRC in Extraocular Muscle Fibrosis of the Graves\u2019 Ophthalmopathy","volume":"8","author":"Hao","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.4049\/jimmunol.1400478","article-title":"Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1","volume":"193","author":"Behnen","year":"2014","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41577-018-0020-8","article-title":"Regulatory mechanisms in T cell receptor signalling","volume":"18","author":"Gaud","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.immuni.2020.03.013","article-title":"Insulin-Like Growth Factors Are Key Regulators of T Helper 17 Regulatory T Cell Balance in Autoimmunity","volume":"52","author":"DiToro","year":"2020","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.4049\/jimmunol.173.5.3564","article-title":"Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves\u2019 disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor","volume":"173","author":"Pritchard","year":"2004","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.4049\/jimmunol.178.5.3281","article-title":"Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves\u2019 disease may carry functional consequences for disease pathogenesis","volume":"178","author":"Douglas","year":"2007","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"113883","DOI":"10.1016\/j.biopha.2022.113883","article-title":"Lenalidomide attenuates IMQ-induced inflammation in a mouse model of psoriasis","volume":"156","author":"Jia","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1007\/s00011-007-7015-4","article-title":"Costunolide inhibits production of tumor necrosis factor-alpha and interleukin-6 by inducing heme oxygenase-1 in RAW264.7 macrophages","volume":"56","author":"Pae","year":"2007","journal-title":"Inflamm. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.intimp.2016.10.006","article-title":"Costunolide, a sesquiterpene lactone, inhibits the differentiation of pro-inflammatory CD4(+) T cells through the modulation of mitogen-activated protein kinases","volume":"40","author":"Park","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2018). EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol., 69, 406\u2013460.","DOI":"10.1016\/j.jhep.2018.08.009"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Niu, X., Wang, X., Niu, B., Meng, Y., He, H., Wang, Y., and Li, G. (2021). Costunolide Loaded in pH-Responsive Mesoporous Silica Nanoparticles for Increased Stability and an Enhanced Anti-Fibrotic Effect. Pharmaceuticals, 14.","DOI":"10.3390\/ph14100951"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New data content and improved web interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"W356","DOI":"10.1093\/nar\/gkx374","article-title":"PharmMapper 2017 update: A web server for potential drug target identification with a comprehensive target pharmacophore database","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: The universal protein knowledgebase in 2021","volume":"49","author":"UniProt","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_58","first-page":"D845","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Pinero","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Abugessaisa, I., and Kasukawa, T. (2021). Practical Guide to Life Science Databases, Springer Nature.","DOI":"10.1007\/978-981-16-5812-9"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_65","unstructured":"(2015). The PyMOL Molecular Graphics System, Schrodinger, LLC.. Version 1.8."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_67","first-page":"47","article-title":"Methods of Blood Collection in the Mouse","volume":"29","author":"Janet","year":"2000","journal-title":"Lab. Animal"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/2\/316\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:39:38Z","timestamp":1760121578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/2\/316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,17]]},"references-count":67,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ph16020316"],"URL":"https:\/\/doi.org\/10.3390\/ph16020316","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,17]]}}}