Cardiac Slc25a49-Mediated Energy Reprogramming Governs Doxorubicin-Induced Cardiomyopathy through the G6P-AP-1-Sln Axis
文献类型： 外文期刊
第一作者： Wan, Sitong
作者： Wan, Sitong;Qi, Jingyi;Xia, Yi;Fan, Chang;Zhang, Xu;Shi, Jiaxin;Wang, Chenxuan;Cheng, Yitong;Zhang, Dongyuan;Liu, Rong;Zhu, Yinhua;An, Peng;Luo, Yongting;Luo, Junjie;Xu, Teng;Cao, Changchang;Jin, Dekui
作者机构：
关键词： cardiomyopathy; doxorubicin; energy reprogramming; mitochondria; Slc25a49-G6P-AP-1-Sln axis
期刊名称：ADVANCED SCIENCE （ 影响因子：14.1； 五年影响因子：15.6 ）
ISSN：
年卷期： 2025 年 12 卷 26 期
页码：
收录情况： SCI
摘要： Doxorubicin (Dox), a potent antitumor drug, is linked to cardiac toxicity. Few mechanism-based therapies against cardiotoxicity are available. Dysfunction in mitochondrial energy metabolism contributes to Dox-induced cardiomyopathy. It is aimed at exploring the association between specific mechanism of energy reprogramming and Dox-induced cardiomyopathy. Cardiac-specific ablation of Slc25a49 mice are generated by crossing Slc25a49(flox/flox) mice with Myh6-Cre mice. Slc25a49(HKO) mice or SLC25A49(KD) cardiomyocytes is treated with Dox. Echocardiography, histological analysis, transmission electron microscopy, bulk RNA sequencing, cell bioenergetic profiling, metabolomics test, chromatin immunoprecipitation, and dual-luciferase reporter assay are conducted to delineate the phenotype and elucidate the molecular mechanisms. Specific ablation of Slc25a49 in cardiomyocytes leads to exacerbated Dox-induced cardiomyopathy, characterized by compromised mitochondrial respiration enhanced glycolysis and increased glycolytic metabolite glucose-6-phosphate (G6P) levels, subsequently activating the activator protein-1 (AP-1) complex. The stimulation of the G6P-AP-1 axis intensifies myocardial damage via transcriptionally regulating Sarcolipin (Sln) expression. Strikingly, targeting of this axis with the AP-1 inhibitor T-5224 effectively improves survival and enhances cardiac function in Dox-induced 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-induced cardiomyopathy through directly modulating G6P-AP-1-Sln axis.
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