文献类型： 外文期刊

作者： Wan, Sitong ¹ ; Qi, Jingyi ¹ ; Xia, Yi ¹ ; Fan, Chang ¹ ; Xu, Teng ² ; Zhang, Xu ¹ ; Shi, Jiaxin ¹ ; Wang, Chenxuan ¹ ; Cheng, Yitong ¹ ; Zhang, Dongyuan ¹ ; Liu, Rong ¹ ; Zhu, Yinhua ¹ ; Cao, Changchang ³ ; Jin, Dekui ⁴ ; An, Peng ¹ ; Luo, Yongting ¹ ; Luo, Junjie ¹ ;

作者机构： 1.China Agr Univ, Dept Nutr & Hlth, Key Lab Precis Nutr & Food Qual, Beijing 100193, Peoples R China

2.Zhejiang Acad Agr Sci, Food Sci Inst, Hangzhou 310021, Peoples R China

3.Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China

4.Chinese Peoples Liberat Army Gen Hosp, Med Ctr 3, Dept Gen Practice, Beijing 100039, Peoples R China

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.