{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:17:47Z","timestamp":1792279067320,"version":"4.4.0"},"reference-count":54,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the University of Minnesota College of Pharmacy S.U.R.R.G.E (Strategic Use of Resources for Revenue Generating Enterprise) Award"},{"name":"the Egyptian Ministry of Higher Education"},{"name":"Fulbright Visiting Scholar Postdoctoral Program, the U.S. Department of State, Bureau of Educational and Cultural Affairs"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Carfilzomib is an irreversible proteasome inhibitor used for multiple myeloma patients. However, carfilzomib treatment is associated with cardiovascular complications. Empagliflozin, an Sodium Glucose Co-transporter 2 inhibitor (SGLT-2) inhibitor, is an oral antidiabetic drug with proven antioxidant and anti-inflammatory properties. The aim of the present study was to determine the cardioprotective effects of empagliflozin against carfilzomib-induced cardiotoxicity. C57BL\/6 mice were randomly divided into four groups: control, empagliflozin, carfilzomib, and carfilzomib + empagliflozin. Empagliflozin prevented carfilzomib-induced cardiotoxicity by ameliorating histological alterations, CK-MB, and troponin-I. Moreover, it inhibited carfilzomib-induced oxidative damage and inflammation via its action on catalase activity, reduced glutathione levels and superoxide dismutase activity, and reduced nuclear factor-\u03baB (p65) and cytokine levels. Mechanistically, empagliflozin abrogated endoplasmic reticulum stress induced by carfilzomib, as evidenced by the effect on the Glucose Regulated Protein-78 (GRP-78)\/Activating Transcription Factor 6 (ATF6)\/C\/EBP homologous protein (CHOP) axis. Intriguingly, carfilzomib significantly induced autophagy, an effect that was further enhanced by empagliflozin, evidenced by increased LC3B and beclin-1 mRNA expression and reduced p62 expression. The effect of empagliflozin on apoptosis was confirmed by reduced expression of active caspase-3. Importantly, empagliflozin did not alter the cytotoxic effect of carfilzomib on human U266B1 multiple myeloma cells. our findings suggest that empagliflozin may provide a new therapeutic strategy to mitigate carfilzomib-induced cardiotoxicity in multiple myeloma patients.<\/jats:p>","DOI":"10.3390\/antiox13060671","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T10:06:01Z","timestamp":1717409161000},"page":"671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Empagliflozin Alleviates Carfilzomib-Induced Cardiotoxicity in Mice by Modulating Oxidative Stress, Inflammatory Response, Endoplasmic Reticulum Stress, and Autophagy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2887-9937","authenticated-orcid":false,"given":"Mina Y.","family":"George","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt"},{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Dabour","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta 31111, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2489-6628","authenticated-orcid":false,"given":"Eman","family":"Rashad","sequence":"additional","affiliation":[{"name":"Department of Cytology and Histology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-4185","authenticated-orcid":false,"given":"Beshay N.","family":"Zordoky","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1053\/j.seminoncol.2016.11.004","article-title":"Multiple myeloma epidemiology and survival: A unique malignancy","volume":"43","author":"Kazandjian","year":"2016","journal-title":"Semin. 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