{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:53:23Z","timestamp":1792511603543,"version":"4.5.0"},"reference-count":67,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Princess Nourah bint Abdulrahman University","award":["PNURSP2025R110"],"award-info":[{"award-number":["PNURSP2025R110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: The cardiotoxic effects of doxorubicin (DOX), a powerful chemotherapeutic drug, are widely recognized. Cuproptosis, a unique copper-dependent form of controlled cell death, may be involved in DOX-induced cardiomyopathy, according to recent findings. This study employs both in vivo and in silico procedures to investigate the protective effects of the copper chelator penicillamine (PEN) and the role of cuproptosis in DOX-related cardiotoxicity. Methods: Thirty-two adult Sprague Dawley rats were allocated into four groups (n = 8): control, DOX, DOX+PEN, and PEN. Cardiac function was assessed via echocardiography. Serum cardiac biomarkers (LDH, CK-MB, CTnI), oxidative stress markers (SOD, GPX, MDA), and expression levels of cuproptosis-related genes (FDX1, LIAS, SLC31A1, ATP7A) were evaluated. Histopathological examinations and immunohistochemical staining for FDX1, SLC31A1, and DLAT were performed. Molecular docking simulated PEN\u2019s interaction with cuproptosis-related proteins. Network pharmacology and molecular docking studies were also conducted to identify core molecular targets and simulate PEN\u2019s binding interactions with key cuproptosis regulators. Results: DOX administration induced significant cardiac dysfunction, oxidative stress, and upregulation of cuproptosis markers. PEN treatment mitigated these effects, improved cardiac function, reduced fibrosis, and suppressed the expression of cuproptosis-related genes and proteins. Docking results confirmed strong interactions between PEN and cuproptosis-regulatory proteins. Network pharmacology revealed 14 key overlapping targets linking PEN with cuproptosis and DOX-induced cardiotoxicity. Conclusion: This study provides experimental evidence implicating cuproptosis in DOX-induced cardiomyopathy. PEN exerts cardioprotection, potentially by targeting this pathway, offering a promising therapeutic strategy.<\/jats:p>","DOI":"10.3390\/biom15091320","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T16:27:33Z","timestamp":1757953653000},"page":"1320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Copper Chelation by Penicillamine Protects Against Doxorubicin-Induced Cardiomyopathy by Suppressing FDX1-Mediated Cuproptosis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2494-6004","authenticated-orcid":false,"given":"Mohammad","family":"El-Nablaway","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Al-Maarefa University, Dariyah 13713, Saudi Arabia"},{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hany M. A.","family":"Sonpol","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7347-4587","authenticated-orcid":false,"given":"Yaser Hosny Ali","family":"Elewa","sequence":"additional","affiliation":[{"name":"Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt"},{"name":"Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0808, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-0262","authenticated-orcid":false,"given":"Mohamed A. M.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0107-7320","authenticated-orcid":false,"given":"Mohamed","family":"Adel","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura National University, Gamasa 35712, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9941-2402","authenticated-orcid":false,"given":"Eman Serry","family":"Zayed","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Alhelf","sequence":"additional","affiliation":[{"name":"Biotechnology School, Nile University, Giza 12588, Egypt"},{"name":"Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6602-6815","authenticated-orcid":false,"given":"Manar A.","family":"Didamoony","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7646-0909","authenticated-orcid":false,"given":"Amal Fahmy","family":"Dawood","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman M.","family":"Embaby","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4825-9885","authenticated-orcid":false,"given":"Khaled S.","family":"El-Bayoumi","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8183-4829","authenticated-orcid":false,"given":"Wesam S.","family":"El-Saeed","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura National University, Gamasa 35712, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1007\/s00210-023-02382-z","article-title":"Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model","volume":"396","author":"Dulf","year":"2023","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. 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