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Few mechanism\u2010based therapies against cardiotoxicity are available. Dysfunction in mitochondrial energy metabolism contributes to Dox\u2010induced cardiomyopathy. It is aimed at exploring the association between specific mechanism of energy reprogramming and Dox\u2010induced cardiomyopathy. Cardiac\u2010specific ablation of\n                    <jats:italic>Slc25a49<\/jats:italic>\n                    mice are generated by crossing\n                    <jats:italic>\n                      Slc25a49\n                      <jats:sup>flox\/flox<\/jats:sup>\n                    <\/jats:italic>\n                    mice with\n                    <jats:italic>Myh6\u2010Cre<\/jats:italic>\n                    mice.\n                    <jats:italic>\n                      Slc25a49\n                      <jats:sup>HKO<\/jats:sup>\n                    <\/jats:italic>\n                    mice or\n                    <jats:italic>\n                      SLC25A49\n                      <jats:sup>KD<\/jats:sup>\n                    <\/jats:italic>\n                    cardiomyocytes is treated with Dox. Echocardiography, histological analysis, transmission electron microscopy, bulk RNA sequencing, cell bioenergetic profiling, metabolomics test, chromatin immunoprecipitation, and dual\u2010luciferase reporter assay are conducted to delineate the phenotype and elucidate the molecular mechanisms. Specific ablation of\n                    <jats:italic>Slc25a49<\/jats:italic>\n                    in cardiomyocytes leads to exacerbated Dox\u2010induced cardiomyopathy, characterized by compromised mitochondrial respiration enhanced glycolysis and increased glycolytic metabolite glucose\u20106\u2010phosphate (G6P) levels, subsequently activating the activator protein\u20101 (AP\u20101) complex. The stimulation of the G6P\u2013AP\u20101 axis intensifies myocardial damage via transcriptionally regulating Sarcolipin (Sln) expression. Strikingly, targeting of this axis with the AP\u20101 inhibitor T\u20105224 effectively improves survival and enhances cardiac function in Dox\u2010induced cardiomyopathy. This study provides mechanistic insights into energy reprogramming that permits myocardial dysfunction, and thus provides a proof of concept for antienergy reprogramming therapy for Dox\u2010induced cardiomyopathy through directly modulating G6P\u2013AP\u20101\u2013Sln axis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202502163","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T14:46:16Z","timestamp":1743864376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cardiac\n                    <i>Slc25a49<\/i>\n                    \u2010Mediated Energy Reprogramming Governs Doxorubicin\u2010Induced Cardiomyopathy through the G6P\u2013AP\u20101\u2013Sln Axis"],"prefix":"10.1002","volume":"12","author":[{"given":"Sitong","family":"Wan","sequence":"first","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing 100193 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Qi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing 100193 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing 100193 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Fan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing 100193 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