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induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg\/kg) and MTX (6 mg\/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments.<\/jats:p>","DOI":"10.3390\/biom13060921","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T03:06:00Z","timestamp":1685588760000},"page":"921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cardiac Molecular Remodeling by Anticancer Drugs: Doxorubicin Affects More Metabolism While Mitoxantrone Impacts More Autophagy in Adult CD-1 Male Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Sofia","family":"Brand\u00e3o","sequence":"first","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory of Toxicology, UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-3147","authenticated-orcid":false,"given":"Ana","family":"Reis-Mendes","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory of Toxicology, UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4727-727X","authenticated-orcid":false,"given":"Margarida","family":"Duarte-Ara\u00fajo","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Department of Imuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Maria","family":"Neuparth","sequence":"additional","affiliation":[{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal"},{"name":"TOXRUN\u2014Toxicology Research Unit, University Institute of Health Sciences, CESPU, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5447-615X","authenticated-orcid":false,"given":"Hugo","family":"Rocha","sequence":"additional","affiliation":[{"name":"Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, 4000-053 Porto, Portugal"},{"name":"Department of Pathological, Cytological and Thanatological Anatomy, School of Health, Polytechnic Institute of Porto, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3494","authenticated-orcid":false,"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory of Toxicology, UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-4051","authenticated-orcid":false,"given":"Rita","family":"Ferreira","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-2756","authenticated-orcid":false,"given":"Vera","family":"Costa","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory of Toxicology, UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1200\/JCO.2003.09.081","article-title":"Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741\/Cancer and Leukemia Group B Trial 9741","volume":"21","author":"Citron","year":"2003","journal-title":"J. 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