{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:02:44Z","timestamp":1785333764743,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Doxorubicin (DOX) is a highly effective chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity, driving the search for protective natural products. Although the herb Viscum coloratum (Kom.) Nakai is known for its cardiovascular benefits, the cardioprotective effects and mechanisms of its isolated compound, DHDK, remain unexplored. Methods: The protective effect of DHDK was first evaluated in DOX-injured H9c2 cardiomyocytes. Subsequently, an integrated network toxicology (incorporating DOX-induced toxicity targets and relevant chronic disease pathways such as aging and lipid metabolism) and pharmacology (DHDK) approach identified core targets, which were then refined through Protein\u2013Protein Interaction (PPI) analysis and molecular docking. The underlying mechanism was investigated using lipidomics and validated through a series of in vitro assays, including CCK-8, q-PCR, biochemical tests, and flow cytometry, as well as in an in vivo rat model. Results: DHDK significantly alleviated DOX-induced cardiomyocyte toxicity. Integrated analysis identified 56 intersecting targets, with PPARG confirmed as the primary target via PPI and molecular docking. Lipidomics revealed that DHDK potently attenuated DOX-induced accumulation of pathogenic lipids (e.g., fatty acids, ceramides). Mechanistically, DHDK activated PPARG, which in turn upregulated CPT1B, a key regulator of fatty acid \u03b2-oxidation (FAO). This enhanced cell viability, ATP production, and mitochondrial membrane potential while reducing oxidative stress. These protective effects, which were abolished by the inhibition of PPARG or CPT1B, were further validated in vivo. Conclusion: This study demonstrates that DHDK exerts its cardioprotective effect by activating the PPARG-CPT1B-FAO axis, effectively correcting lipid metabolic disorders. Given that lipid dysregulation is a hallmark of various internal metabolic diseases, DHDK may also hold therapeutic potential for other heart conditions driven by metabolic disturbances, such as diabetic cardiomyopathy, highlighting its broad relevance to the field of internal diseases.<\/jats:p>","DOI":"10.3390\/ph18111759","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T16:49:51Z","timestamp":1763484591000},"page":"1759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DHDK, a Plant-Derived Natural Small Molecule, Protects Against Doxorubicin-Induced Cardiotoxicity via the PPARG-CPT1B-FAO Axis"],"prefix":"10.3390","volume":"18","author":[{"given":"Jing","family":"Hong","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyang","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongang","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamei","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyang","family":"L\u00fc","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Medical Devices, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-2811","authenticated-orcid":false,"given":"Yunli","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Gieleci\u0144ska, A., Mujwar, S., Ko\u0142at, D., Ka\u0142uzi\u0144ska-Ko\u0142at, \u017b., Celik, I., and Kontek, R. (2023). Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity. Cells, 12.","DOI":"10.3390\/cells12040659"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.trecan.2024.05.005","article-title":"Chromatin as an old and new anticancer target","volume":"10","author":"Neefjes","year":"2024","journal-title":"Trend Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1007\/s00204-016-1759-y","article-title":"Pathways of cardiac toxicity: Comparison between chemotherapeutic drugs doxorubicin and mitoxantrone","volume":"90","author":"Damiani","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.jacc.2009.03.095","article-title":"Anthracycline-induced cardiomyopathy: Clinical relevance and response to pharmacologic therapy","volume":"55","author":"Cardinale","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1200\/JCO.23.01779","article-title":"Cardiac Dysfunction Among Breast Cancer Survivors: Role of Cardiotoxic Therapy and Cardiovascular Risk Factors","volume":"43","author":"Bostany","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1093\/jnci\/djae107","article-title":"Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors","volume":"116","author":"Vo","year":"2024","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.jatmed.2024.11.003","article-title":"Neoadjuvant chemotherapy and perioperative cardiotoxicity","volume":"3","author":"Tu","year":"2024","journal-title":"J. Anesth. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Palmieri, V., Vietri, M.T., Montalto, A., Montisci, A., Donatelli, F., Coscioni, E., and Napoli, C. (2023). Cardiotoxicity, Cardioprotection, and Prognosis in Survivors of Anticancer Treatment Undergoing Cardiac Surgery: Unmet Needs. Cancers, 15.","DOI":"10.3390\/cancers15082224"},{"key":"ref_9","first-page":"e37308","article-title":"Efficacy of Dexrazoxane in Cardiac Protection in Pediatric Patients Treated with Anthracyclines","volume":"15","author":"Rahimi","year":"2023","journal-title":"Cureus"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"357","DOI":"10.2147\/CMAR.S47238","article-title":"Dexrazoxane for the treatment of chemotherapy-related side effects","volume":"6","author":"Langer","year":"2014","journal-title":"Cancer Manag. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lee, S.R., Mukae, M., Jeong, K.J., Park, S.H., Shin, H.J., Kim, S.W., Won, Y.S., Kwun, H.J., Baek, I.J., and Hong, E.J. (2023). PGRMC1 Ablation Protects from Energy-Starved Heart Failure by Promoting Fatty Acid\/Pyruvate Oxidation. Cells, 12.","DOI":"10.3390\/cells12050752"},{"key":"ref_12","first-page":"S11","article-title":"Fatty acid oxidation in the heart","volume":"28","author":"Grynberg","year":"1996","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e36834","DOI":"10.1016\/j.heliyon.2024.e36834","article-title":"Pera orange juice (Citrus sinensis L. Osbeck) alters lipid metabolism and attenuates oxidative stress in the heart and liver of rats treated with doxorubicin","volume":"10","author":"Cabral","year":"2024","journal-title":"Heliyon"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1007\/s12012-022-09725-x","article-title":"Exploring the Pattern of Metabolic Alterations Causing Energy Imbalance via PPAR\u03b1 Dysregulation in Cardiac Muscle During Doxorubicin Treatment","volume":"22","author":"Renu","year":"2022","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wang, S., Zhang, X., Hou, Y., Zhang, Y., Chen, J., Gao, S., Duan, H., Gu, S., Yu, S., and Cai, Y. (2024). SIRT6 activates PPAR\u03b1 to improve doxorubicin-induced myocardial cell aging and damage. Chem. Biol. Interact., 392.","DOI":"10.1016\/j.cbi.2024.110920"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.freeradbiomed.2025.02.021","article-title":"Overexpression of hnRNPK and inhibition of cytoplasmic translocation ameliorate lipid disorder in doxorubicin-induced cardiomyopathy via PINK1\/Parkin-mediated mitophagy","volume":"231","author":"Xu","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, S., Wei, X., Zhang, H., Wu, Y., Jing, J., Huang, R., Zhou, T., Hu, J., Wu, Y., and Li, Y. (2023). Doxorubicin downregulates autophagy to promote apoptosis-induced dilated cardiomyopathy via regulating the AMPK\/mTOR pathway. Biomed. Pharmacother., 162.","DOI":"10.1016\/j.biopha.2023.114691"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Li, W., Cao, J., Wang, X., Zhang, Y., Sun, Q., Jiang, Y., Yao, J., Li, C., Wang, Y., and Wang, W. (2021). Ferruginol Restores SIRT1-PGC-1\u03b1-Mediated Mitochondrial Biogenesis and Fatty Acid Oxidation for the Treatment of DOX-Induced Cardiotoxicity. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.773834"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9576","DOI":"10.1039\/D2FO00772J","article-title":"Daidzein alleviates doxorubicin-induced heart failure via the SIRT3\/FOXO3a signaling pathway","volume":"13","author":"Li","year":"2022","journal-title":"Food Funct."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/s41569-023-00881-3","article-title":"Hallmarks of cardiovascular ageing","volume":"20","author":"Abdellatif","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nrcardio.2016.203","article-title":"Mitochondrial function as a therapeutic target in heart failure","volume":"14","author":"Brown","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cbi.2019.01.032","article-title":"Oxidized phospholipids in Doxorubicin-induced cardiotoxicity","volume":"303","author":"Koleini","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s10741-020-09968-2","article-title":"Anthracycline-induced cardiotoxicity: Mechanisms of action, incidence, risk factors, prevention, and treatment","volume":"26","author":"Saleh","year":"2021","journal-title":"Heart Fail. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1515\/znc-2012-3-404","article-title":"Cytotoxic constituents of Viscum coloratum","volume":"67","author":"Zhao","year":"2012","journal-title":"Z. Naturforsch C J. Biosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114233","DOI":"10.1016\/j.jep.2021.114233","article-title":"Exploring the resources of the genus Viscum for potential therapeutic applications","volume":"277","author":"Song","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_26","unstructured":"(2025, July 05). Anthracycline Global Market Report 2025\u2014By Drugs (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Val-rubicin), By Dosage (Powder, Capsule, Solution, Injection, Suspension, Other Dosages), By Application (Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Hodgkin\u2019s Lymphoma, Non-Hodgkin\u2019s Lymphoma, Bladder Cancer, Breast Cancer, Other Metastatic Cancers), By End User (Hospitals, Homecare, Specialty Clinics, Other End Users)\u2014Market Size, Trends, And Global Forecast 2025\u20132034. Available online: https:\/\/www.thebusinessresearchcompany.com\/report\/anthracycline-global-market-report."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nebigil, C.G., and D\u00e9saubry, L. (2018). Updates in Anthracycline-Mediated Cardiotoxicity. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01262"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1038\/s41467-023-39607-x","article-title":"Ultrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity","volume":"14","author":"Wang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41556-020-0507-y","article-title":"Overcoming Wnt-\u03b2-catenin dependent anticancer therapy resistance in leukaemia stem cells","volume":"22","author":"Perry","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s43044-025-00628-0","article-title":"Cardiomyopathies and a brief insight into DOX-induced cardiomyopathy","volume":"77","author":"Tanwar","year":"2025","journal-title":"Egypt. Heart J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/cvr\/cvn098","article-title":"Transcriptional control of mitochondrial biogenesis: The central role of PGC-1alpha","volume":"79","author":"Garnier","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7983","DOI":"10.1039\/C9FO02159K","article-title":"Curcumin inhibits cigarette smoke-induced inflammation via modulating the PPAR\u03b3-NF-\u03baB signaling pathway","volume":"10","author":"Li","year":"2019","journal-title":"Food Funct."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1002\/hep.28000","article-title":"Stimulation of nuclear receptor peroxisome proliferator-activated receptor-\u03b3 limits NF-\u03baB-dependent inflammation in mouse cystic fibrosis biliary epithelium","volume":"62","author":"Scirpo","year":"2015","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"111758","DOI":"10.1016\/j.mad.2022.111758","article-title":"Pathological implication of CaMKII in NF-\u03baB pathway and SASP during cardiomyocytes senescence","volume":"209","author":"Li","year":"2023","journal-title":"Mech. Ageing Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00232-010-9297-7","article-title":"Stimulation of ENaC activity by rosiglitazone is PPAR\u03b3-dependent and correlates with SGK1 expression increase","volume":"236","author":"Renauld","year":"2010","journal-title":"J. Membr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27794","DOI":"10.1039\/D0RA03674A","article-title":"Novel drug isolated from mistletoe (1E,4E)-1,7-bis(4-hydroxyphenyl)hepta-1,4-dien-3-one for potential treatment of various cancers: Synthesis, pharmacokinetics and pharmacodynamics","volume":"10","author":"Hong","year":"2020","journal-title":"RSC Adv."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"W609","DOI":"10.1093\/nar\/gkq300","article-title":"PharmMapper server: A web server for potential drug target identification using pharmacophore mapping approach","volume":"38","author":"Liu","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1021\/acs.jcim.5b00690","article-title":"Enhancing the Enrichment of Pharmacophore-Based Target Prediction for the Polypharmacological Profiles of Drugs","volume":"56","author":"Wang","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"D1328","DOI":"10.1093\/nar\/gkae883","article-title":"Comparative Toxicogenomics Database\u2019s 20th anniversary: Update 2025","volume":"53","author":"Davis","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D1398","DOI":"10.1093\/nar\/gkab953","article-title":"Therapeutic target database update 2022: Facilitating drug discovery with enriched comparative data of targeted agents","volume":"50","author":"Zhou","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1.30","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_44","unstructured":"The GeneCards Suite (2025, May 18). Practical Guide to Life Science Databases 27\u201356. Available online: https:\/\/www.genecards.org."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"W513","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"W257","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: A webserver for the prediction of toxicity of chemicals","volume":"46","author":"Banerjee","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_48","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_49","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_50","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_51","doi-asserted-by":"crossref","first-page":"iyad031","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Aleksander","year":"2023","journal-title":"Genetics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8.14.1","DOI":"10.1002\/0471250953.bi0814s24","article-title":"Using AutoDock for ligand-receptor docking","volume":"24","author":"Morris","year":"2008","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_55","unstructured":"(2025, June 07). PyMOL by Schr\u00f6dinger. Available online: http:\/\/www.pymol.org\/pymol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e2100240","DOI":"10.1002\/minf.202100240","article-title":"A Descriptor Set for Quantitative Structure-property Relationship Prediction in Biologics","volume":"41","author":"Sankar","year":"2022","journal-title":"Mol. Inform."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Tavella, D., Ouellette, D.R., Garofalo, R., Zhu, K., Xu, J., Oloo, E.O., Negron, C., and Ihnat, P.M. (2022). A novel method for in silico assessment of Methionine oxidation risk in monoclonal antibodies: Improvement over the 2-shell model. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0279689"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1002\/prot.25594","article-title":"AggScore: Prediction of aggregation-prone regions in proteins based on the distribution of surface patches","volume":"86","author":"Sankar","year":"2018","journal-title":"Proteins"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1002\/prot.24551","article-title":"Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction","volume":"82","author":"Zhu","year":"2014","journal-title":"Proteins"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1093\/protein\/gzu017","article-title":"Structure-based approach to the prediction of disulfide bonds in proteins","volume":"27","author":"Salam","year":"2014","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Beard, H., Cholleti, A., Pearlman, D., Sherman, W., and Loving, K.A. (2013). Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082849"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Wang, L., Zhang, T.P., Zhang, Y., Bi, H.L., Guan, X.M., Wang, H.X., Wang, X., Du, J., Xia, Y.L., and Li, H.H. (2016). Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein. Sci. Rep., 6.","DOI":"10.1038\/srep28399"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Maillet, A., Tan, K., Chai, X., Sadananda, S.N., Mehta, A., Ooi, J., Hayden, M.R., Pouladi, M.A., Ghosh, S., and Shim, W. (2016). Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes. Sci. Rep., 6.","DOI":"10.1038\/srep25333"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.stemcr.2022.03.002","article-title":"RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes","volume":"17","author":"Huang","year":"2022","journal-title":"Stem Cell Rep."},{"key":"ref_65","first-page":"2576","article-title":"Study on the model of chronic heart failure induced by adriamycin in rats","volume":"41","author":"Yixin","year":"2021","journal-title":"Chin. J. Gerontol."},{"key":"ref_66","first-page":"330","article-title":"Effects of portulaca polysaccharide on atheroscleroti plaque in rats by regulating PPAR\u03b3\/NF\u03baB pathway","volume":"45","author":"Liping","year":"2023","journal-title":"Hebei Med. J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1939-165X.2012.00418.x","article-title":"Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research","volume":"41","author":"Kilkenny","year":"2012","journal-title":"Vet. Clin. Pathol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1759\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:04:50Z","timestamp":1763543090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1759"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,18]]},"references-count":67,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ph18111759"],"URL":"https:\/\/doi.org\/10.3390\/ph18111759","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,18]]}}}