{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:36:54Z","timestamp":1792467414970,"version":"4.5.0"},"reference-count":71,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007446","name":"King Khalid University","doi-asserted-by":"publisher","award":["RGP2\/87\/46"],"award-info":[{"award-number":["RGP2\/87\/46"]}],"id":[{"id":"10.13039\/501100007446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Doxorubicin (Dox) is a potent anthracycline antitumor drug whose clinical utility is significantly restricted by its dose-dependent, cumulative cardiotoxicity, driven by increased oxidative stress, impaired antioxidant defenses, and apoptosis-mediated cardiomyocyte loss. Methylene blue (MB), a phenothiazine derivative with well-documented redox-modulating properties, is being explored as a viable cardioprotective agent due to its antioxidant and anti-apoptotic effects. This study evaluated the protective role of MB against Dox-induced cardiotoxicity in rats by examining its impact on oxidative stress markers (Kelch-like ECH-associated protein 1; KEAP1, nuclear factor erythroid 2-related factor 2; NRF2, Glutathione peroxidase 4; GPX-4, 8-hydroxy-2\u2032-deoxyguanosine; 8-OHdG), neurohormonal indicators (noradrenaline), cardiac injury biomarkers (troponin I), and apoptotic mediators (p53, Caspase-3). Forty male albino rats were divided equally into four groups: control, Dox (15 mg\/kg, i.p.), MB alone (4 mg\/kg\/day, p.o. for 7 days), and Dox plus MB. Dox administration significantly increased serum troponin I and noradrenaline levels, elevated cardiac KEAP1 and 8-OHdG, and reduced NFE2L2, NRF2, and GPX-4 expression. It also upregulated p53 and Caspase-3 and caused marked myocardial degeneration, necrosis, and inflammatory infiltration. MB co-treatment significantly reduced troponin I and noradrenaline levels, restored KEAP1\/NFE2L2 (NRF2)\/GPX-4 pathway balance, decreased oxidative DNA damage, and attenuated p53 and Caspase-3 activation, preserving myocardial architecture with minimal inflammatory changes. These findings demonstrate that MB confers potent cardioprotection against Dox-induced cardiac injury by enhancing antioxidant defenses, limiting oxidative DNA damage, suppressing apoptosis, and normalizing neurohormonal imbalance, suggesting its promise as an adjunctive strategy to mitigate anthracycline-associated cardiotoxicity.<\/jats:p>","DOI":"10.3390\/ijms26167680","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T11:41:53Z","timestamp":1754653313000},"page":"7680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Methylene Blue Mitigates Doxorubicin-Induced Cardiotoxicity via KEAP1\/NRF2\/GPX-4\/Caspase3 Modulation"],"prefix":"10.3390","volume":"26","author":[{"given":"Shaimaa G.","family":"Ibrahim","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-9011","authenticated-orcid":false,"given":"Ahmed M.","family":"Abu-Dief","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt"},{"name":"Department of Chemistry, College of Science, Taibah University, Madinah P.O. Box 344, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6175-184X","authenticated-orcid":false,"given":"Amany M.","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia 41636, Egypt"},{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)-Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0338-6530","authenticated-orcid":false,"given":"Enas S.","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia 41636, Egypt"},{"name":"Department of Pharmaceutical Sciences, King Faisal University, Al-Ahsa 13889, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5231-8932","authenticated-orcid":false,"given":"Abdullah Yahya Abdullah","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, King Khalid University, Abha 61413, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alhafez M.","family":"Alraih","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, King Khalid University, Abha 61413, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim Omar","family":"Barnawi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, Taibah University, Al-Madinah Al-Munawwarah 41321, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Mansour","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1976-9480","authenticated-orcid":false,"given":"Mohamed H. A.","family":"Gadelmawla","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Dentistry, Sinai University, Kantara Branch, Ismailia 41636, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Khames","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sohag University, Sohag 82511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1053\/j.seminoncol.2005.11.001","article-title":"Anticancer Agents and Cardiotoxicity","volume":"33","author":"Ng","year":"2006","journal-title":"Semin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.2042-7158.2012.01567.x","article-title":"Doxorubicin: An Update on Anticancer Molecular Action, Toxicity and Novel Drug Delivery Systems","volume":"65","author":"Tacar","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"44","DOI":"10.2174\/1389557516666160621083659","article-title":"Pharmaceutical Measures to Prevent Doxorubicin-Induced Cardiotoxicity","volume":"17","author":"Liu","year":"2017","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.pcad.2006.10.002","article-title":"Doxorubicin-Induced Cardiomyopathy from the Cardiotoxic Mechanisms to Management","volume":"49","author":"Takemura","year":"2007","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1067\/mnc.2000.103324","article-title":"Cardiotoxicity of Doxorubicin and Other Anthracycline Derivatives","volume":"7","author":"Jain","year":"2000","journal-title":"J. Nucl. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"748524","DOI":"10.1155\/2014\/748524","article-title":"Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction","volume":"2014","author":"Li","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1042\/bj20020752","article-title":"Activation of Nuclear Factor-kappaB during Doxorubicin-Induced Apoptosis in Endothelial Cells and Myocytes Is pro-Apoptotic: The Role of Hydrogen Peroxide","volume":"367","author":"Wang","year":"2002","journal-title":"Biochem. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3892\/mmr.2013.1554","article-title":"Activation of the P38 MAPK\/NF-\u03baB Pathway Contributes to Doxorubicin-Induced Inflammation and Cytotoxicity in H9c2 Cardiac Cells","volume":"8","author":"Guo","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_9","first-page":"345","article-title":"Effects of oxymatrine on expression of nuclear factor kappa B in kidneys of rats with adriamycin-induced chronic renal fibrosis","volume":"27","author":"Chen","year":"2007","journal-title":"J. South. Med. Univ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1159\/000265166","article-title":"Doxorubicin Cardiomyopathy","volume":"115","author":"Chatterjee","year":"2010","journal-title":"Cardiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/sj.bjp.0703959","article-title":"Chronic Vascular Toxicity of Doxorubicin in an Organ-Cultured Artery","volume":"132","author":"Murata","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1152\/japplphysiol.00967.2017","article-title":"Methylene Blue Counteracts Cyanide Cardiotoxicity: Cellular Mechanisms","volume":"124","author":"Cheung","year":"2018","journal-title":"J. Appl. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R1030","DOI":"10.1152\/ajpregu.00527.2015","article-title":"Methylene Blue Counteracts H2S Toxicity-Induced Cardiac Depression by Restoring L-Type Ca Channel Activity","volume":"310","author":"Zhang","year":"2016","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Barbosa Evora, P.R., Celotto, A.C., Sumarelli Albuquerque, A.A., and Martinez \u00c9vora, P. (2021). Methylene Blue. Vasoplegic Endothelial Dysfunction: Circulatory Shock and Methylene Blue, Springer International Publishing.","DOI":"10.1007\/978-3-030-74096-2"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.athoracsur.2017.02.057","article-title":"Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival","volume":"104","author":"Mehaffey","year":"2017","journal-title":"Ann. Thorac. Surg."},{"key":"ref_16","first-page":"744470","article-title":"Methylene Blue as an Adjuvant during Cardiopulmonary Resuscitation: An Experimental Study in Rats","volume":"74","author":"Xavier","year":"2024","journal-title":"Braz. J. Anesthesiol."},{"key":"ref_17","first-page":"E2","article-title":"Experimental Neuroprotection in Ischemic Stroke: A Concise Review","volume":"42","author":"Rajah","year":"2017","journal-title":"Neurosurg. Focus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1213\/ANE.0000000000001045","article-title":"Methylene Blue: Magic Bullet for Vasoplegia?","volume":"122","author":"Hosseinian","year":"2016","journal-title":"Anesth. Analg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3233\/CH-141874","article-title":"Impact of Methylene Blue in Addition to Norepinephrine on the Intestinal Microcirculation in Experimental Septic Shock","volume":"58","author":"Nantais","year":"2014","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Werner, I., Guo, F., Bogert, N.V., Stock, U.A., Meybohm, P., Moritz, A., and Beiras-Fernandez, A. (2013). Methylene Blue Modulates Transendothelial Migration of Peripheral Blood Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082214"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1590\/S0066-782X2006001700019","article-title":"Hemodynamic and Vascular Endothelium Function Studies in Healthy Pigs After Intravenous Bolus Infusion of Methylene Blue","volume":"87","author":"Menardi","year":"2006","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_22","first-page":"115","article-title":"Nitric Oxide Synthase Inhibitors","volume":"36","author":"Siriwardena","year":"2000","journal-title":"Methods Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16504","DOI":"10.1074\/jbc.M110.208447","article-title":"Alternative Mitochondrial Electron Transfer as a Novel Strategy for Neuroprotection","volume":"286","author":"Wen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1007\/s12640-009-9027-z","article-title":"Methylene Blue Provides Behavioral and Metabolic Neuroprotection Against Optic Neuropathy","volume":"15","author":"Rojas","year":"2009","journal-title":"Neurotox. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1177\/0885066606290671","article-title":"Use of Methylene Blue in Sepsis: A Systematic Review","volume":"21","author":"Kwok","year":"2006","journal-title":"J. Intensive Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.2174\/1871520621666201229115612","article-title":"The Synthesis of Nano-Doxorubicin and Its Anticancer Effect","volume":"21","author":"Zhu","year":"2021","journal-title":"Anticancer. Agents Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Rawat, P.S., Jaiswal, A., Khurana, A., Bhatti, J.S., and Navik, U. (2021). Doxorubicin-Induced Cardiotoxicity: An Update on the Molecular Mechanism and Novel Therapeutic Strategies for Effective Management. Biomed. Pharmacother., 139.","DOI":"10.1016\/j.biopha.2021.111708"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jaccao.2023.03.012","article-title":"Evaluation of Senescence and Its Prevention in Doxorubicin-Induced Cardiotoxicity Using Dynamic Engineered Heart Tissues","volume":"5","author":"Linders","year":"2023","journal-title":"JACC CardioOncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s11010-023-04783-3","article-title":"Novel Molecular Mechanisms of Doxorubicin Cardiotoxicity: Latest Leading-Edge Advances and Clinical Implications","volume":"479","author":"Traore","year":"2024","journal-title":"Mol. Cell Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sorodoc, V., Sirbu, O., Lionte, C., Haliga, R.E., Stoica, A., Ceasovschih, A., Petris, O.R., Constantin, M., Costache, I.I., and Petris, A.O. (2022). The Value of Troponin as a Biomarker of Chemotherapy-Induced Cardiotoxicity. Life, 12.","DOI":"10.3390\/life12081183"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/jcb.29840","article-title":"A Short Review: Doxorubicin and Its Effect on Cardiac Proteins","volume":"122","author":"Upadhyay","year":"2021","journal-title":"J. Cell Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12964-023-01077-5","article-title":"Role of Oxidative Stress and Inflammation-Related Signaling Pathways in Doxorubicin-Induced Cardiomyopathy","volume":"21","author":"Shi","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Vitale, R., Marzocco, S., and Popolo, A. (2024). Role of Oxidative Stress and Inflammation in Doxorubicin-Induced Cardiotoxicity: A Brief Account. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202405.1681.v1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107683","DOI":"10.1016\/j.carpath.2024.107683","article-title":"Doxorubicin-Related Cardiotoxicity: Review of Fundamental Pathways of Cardiovascular System Injury","volume":"73","author":"Avagimyan","year":"2024","journal-title":"Cardiovasc. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhang, H., Liu, Y., Zhang, K., Hong, Z., Liu, Z., Liu, Z., Li, G., Xu, Y., Pi, J., and Fu, J. (2024). Understanding the Transcription Factor NFE2L1\/NRF1 from the Perspective of Hallmarks of Cancer. Antioxidants, 13.","DOI":"10.3390\/antiox13070758"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e37326","DOI":"10.1016\/j.heliyon.2024.e37326","article-title":"The Role of KEAP1-Nrf2 Signaling Pathway in the Treatment of Respiratory Diseases and the Research Progress on Targeted Drugs","volume":"10","author":"Zhang","year":"2024","journal-title":"Heliyon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.14348\/molcells.2023.0005","article-title":"Anti-Ferroptotic Effects of Nrf2: Beyond the Antioxidant Response","volume":"46","author":"Shakya","year":"2023","journal-title":"Mol. Cells"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Baiskhanova, D., and Sch\u00e4fer, H. (2024). The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer. Antioxidants, 13.","DOI":"10.3390\/antiox13060696"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1080\/13506129.2021.1966624","article-title":"Patients with Cardiac Amyloidosis Have a Greater Neurohormonal Activation than Those with Non-Amyloidotic Heart Failure","volume":"28","author":"Vergaro","year":"2021","journal-title":"Amyloid"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.jjcc.2021.11.016","article-title":"Heart Failure and Its Treatment from the Perspective of Sympathetic Nerve Activity","volume":"79","author":"Minatoguchi","year":"2022","journal-title":"J. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.31083\/j.rcm2204130","article-title":"Catecholamine-Induced Cardiomyopathy: An Endocrinologist\u2019s Perspective","volume":"22","author":"Kumar","year":"2021","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"373","DOI":"10.4330\/wjc.v12.i8.373","article-title":"Sympathetic Nervous System Activation and Heart Failure: Current State of Evidence and the Pathophysiology in the Light of Novel Biomarkers","volume":"12","author":"Borovac","year":"2020","journal-title":"World J. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/j.2040-4603.2016.tb00669.x","article-title":"Pathophysiology of Heart Failure","volume":"6","author":"Tanai","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1093\/cvr\/cvab222","article-title":"Central and Peripheral Sympathetic Activation in Heart Failure","volume":"118","author":"Grassi","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9412","DOI":"10.1039\/D3NR06269D","article-title":"Novel PLGA-Based Nanoformulation Decreases Doxorubicin-Induced Cardiotoxicity","volume":"16","author":"Beus","year":"2024","journal-title":"Nanoscale"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Goje, I.-D., Goje, G.-I., Ordodi, V.L., Ciobotaru, V.G., Ivan, V.S., Buza\u0219, R., Tunea, O., Bojin, F., and Lighezan, D.-F. (2025). Doxorubicin-Induced Cardiotoxicity and the Emerging Role of SGLT2 Inhibitors: From Glycemic Control to Cardio-Oncology. Pharmaceuticals, 18.","DOI":"10.3390\/ph18050681"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1007\/s00204-022-03241-1","article-title":"Sacubitril\/Valsartan Reduces Endoplasmic Reticulum Stress in a Rat Model of Doxorubicin-Induced Cardiotoxicity","volume":"96","author":"Kim","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Dalimunthe, A., Satria, D., Sitorus, P., Harahap, U., Angela, I.F.D., and Waruwu, S.B. (2024). Cardioprotective Effect of Hydroalcohol Extract of Andaliman (Zanthoxylum acanthopodium DC.) Fruits on Doxorubicin-Induced Rats. Pharmaceuticals, 17.","DOI":"10.3390\/ph17030359"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"120792","DOI":"10.1016\/j.lfs.2022.120792","article-title":"Protective Effect of Green Synthesized Selenium Nanoparticles against Doxorubicin Induced Multiple Adverse Effects in Swiss Albino Mice","volume":"305","author":"Khan","year":"2022","journal-title":"Life Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.25122\/jml-2023-0091","article-title":"Assessing the Cardioprotective Effect of Necrosulfonamide in Doxorubicin-Induced Cardiotoxicity in Mice","volume":"16","author":"Abbas","year":"2023","journal-title":"J. Med. Life"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s00213-023-06357-z","article-title":"Curcumin Protects Against Doxorubicin Induced Oxidative Stress by Regulating the KEAP1-Nrf2-ARE and Autophagy Signaling Pathways","volume":"240","author":"Liao","year":"2023","journal-title":"Psychopharmacology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"156684","DOI":"10.1016\/j.phymed.2025.156684","article-title":"Erianin Alleviates Doxorubicin-Induced Cardiotoxicity by Activating the KEAP1-Nrf2 Signaling Pathway","volume":"141","author":"Kang","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Shan, W., Liu, G., Deng, C., Wei, Y., and Ding, K. (2024). Chlorogenic Acid Mitigates Ferroptosis by Activating the Nrf2\/GPX4 Pathway through KEAP1 Blockade in Vascular Dementia Rats. J. Food Biochem., 2024.","DOI":"10.1155\/2024\/7848982"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1023\/A:1015976430790","article-title":"Doxorubicin-Induced Apoptosis: Implications in Cardiotoxicity","volume":"234\u2013235","author":"Kalyanaraman","year":"2002","journal-title":"Mol. Cell Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s10565-021-09649-2","article-title":"Sirt6 Protects Cardiomyocytes against Doxorubicin-Induced Cardiotoxicity by Inhibiting P53\/Fas-Dependent Cell Death and Augmenting Endogenous Antioxidant Defense Mechanisms","volume":"39","author":"Wu","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"ref_56","first-page":"2948","article-title":"Sodium Thiosulphate Shows Promising Anti-Inflammatory Role against Doxorubicin-Induced Renal Injury Depending on Tlr4 Pathway Inhibition","volume":"20","author":"Khames","year":"2020","journal-title":"Plant Arch."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/S0003-4975(03)01510-8","article-title":"Methylene Blue Reduces Mortality and Morbidity in Vasoplegic Patients after Cardiac Surgery","volume":"77","author":"Levin","year":"2004","journal-title":"Ann. Thorac. Surg."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ajem.2023.08.041","article-title":"The Effects of Methylene Blue during and after Cardiac Arrest in a Porcine Model; a Randomized, Blinded, Placebo-Controlled Study","volume":"73","author":"Johannsen","year":"2023","journal-title":"Am. J. Emerg. Med."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Samoylova, N.A., Gureev, A.P., and Popov, V.N. (2023). Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076118"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41401-021-00646-z","article-title":"Methylene Blue Prevents Osteoarthritis Progression and Relieves Pain in Rats via Upregulation of Nrf2\/PRDX1","volume":"43","author":"Li","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Poteet, E., Winters, A., Yan, L.-J., Shufelt, K., Green, K.N., Simpkins, J.W., Wen, Y., and Yang, S.-H. (2012). Neuroprotective Actions of Methylene Blue and Its Derivatives. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048279"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Krutskikh, E.P., Potanina, D.V., Samoylova, N.A., Gryaznova, M.V., Sadovnikova, I.S., Gureev, A.P., and Popov, V.N. (2022). Brain Protection by Methylene Blue and Its Derivative, Azur B, via Activation of the Nrf2\/ARE Pathway in Cisplatin-Induced Cognitive Impairment. Pharmaceuticals, 15.","DOI":"10.3390\/ph15070815"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Jiang, Z., Watts, L.T., Huang, S., Shen, Q., Rodriguez, P., Chen, C., Zhou, C., and Duong, T.Q. (2015). The Effects of Methylene Blue on Autophagy and Apoptosis in MRI-Defined Normal Tissue, Ischemic Penumbra and Ischemic Core. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131929"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"S439","DOI":"10.3233\/JAD-2010-100414","article-title":"Protective Role of Methylene Blue in Alzheimer\u2019s Disease via Mitochondria and Cytochrome c Oxidase","volume":"20","author":"Atamna","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.intimp.2015.04.044","article-title":"Methylene Blue Attenuates Acute Liver Injury Induced by Paraquat in Rats","volume":"28","author":"Chen","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1179\/joc.2002.14.5.431","article-title":"Methylene Blue\u2014A Therapeutic Dye for All Seasons?","volume":"14","author":"Wainwright","year":"2002","journal-title":"J. Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ejphar.2014.01.065","article-title":"Chrysin Alleviates Acute Doxorubicin Cardiotoxicity in Rats via Suppression of Oxidative Stress, Inflammation and Apoptosis","volume":"728","author":"Mantawy","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_68","first-page":"e13850","article-title":"The Ameliorative Effects of Methylene Blue on Testicular Damage Induced by Cisplatin in Rats","volume":"53","author":"Yari","year":"2021","journal-title":"Andrologia"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Alrashdi, B.M., Askar, H., Germoush, M.O., Fouda, M., Massoud, D., Alzwain, S., Abdelsater, N., Salim, L.M.S., Gadelmawla, M.H.A., and Ashry, M. (2025). Cardioprotective, Anti-Inflammatory, and Antioxidative Outcome of Costus against Bleomycin-Induced Cardiotoxicity in Rat Model. J. Genet. Eng. Biotechnol., 23.","DOI":"10.1016\/j.jgeb.2025.100466"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Arab, H.H., Alsufyani, S.E., Ashour, A.M., Gad, A.M., Elhemiely, A.A., Gadelmawla, M.H.A., Mahmoud, M.A., and Khames, A. (2024). Targeting JAK2\/STAT3, NLRP3\/Caspase-1, and PK2\/PKR2 Pathways with Arbutin Ameliorates Lead Acetate-Induced Testicular Injury in Rats. Pharmaceuticals, 17.","DOI":"10.3390\/ph17070909"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00580-023-03510-0","article-title":"Nano-Chitosan\/Bovine Lactoperoxidase and Lactoferrin Formulation Modulates the Hepatic Deterioration Induced by 7,12-Dimethylbenz[a]Anthracene","volume":"32","author":"Ashry","year":"2023","journal-title":"Comp. Clin. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7680\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:26:30Z","timestamp":1760034390000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":71,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26167680"],"URL":"https:\/\/doi.org\/10.3390\/ijms26167680","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]}}}