Wan Sitong, Qi Jingyi, Xia Yi, Fan Chang, Xu Teng, Zhang Xu, Shi Jiaxin, Wang Chenxuan, Cheng Yitong, Zhang Dongyuan, Liu Rong, Zhu Yinhua, Cao Changchang, Jin Dekui, An Peng, Luo Yongting, Luo Junjie
Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100193, China.
Food Science Institute, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China.
Adv Sci (Weinh). 2025 Jul;12(26):e2502163. doi: 10.1002/advs.202502163. Epub 2025 Apr 4.
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 mice with Myh6-Cre mice. Slc25a49 mice or SLC25A49 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.
阿霉素（Dox）是一种强效抗肿瘤药物，与心脏毒性有关。针对心脏毒性的基于机制的治疗方法很少。线粒体能量代谢功能障碍导致阿霉素诱导的心肌病。旨在探索能量重编程的特定机制与阿霉素诱导的心肌病之间的关联。通过将Slc25a49小鼠与Myh6-Cre小鼠杂交，产生心脏特异性敲除Slc25a49的小鼠。用阿霉素处理Slc25a49小鼠或SLC25A49心肌细胞。进行超声心动图、组织学分析、透射电子显微镜、批量RNA测序、细胞生物能量分析、代谢组学测试、染色质免疫沉淀和双荧光素酶报告基因测定，以描述表型并阐明分子机制。心肌细胞中Slc25a49的特异性敲除导致阿霉素诱导的心肌病加重，其特征是线粒体呼吸受损、糖酵解增强和糖酵解代谢产物葡萄糖-6-磷酸（G6P）水平升高，随后激活激活蛋白-1（AP-1）复合物。G6P-AP-1轴的刺激通过转录调节肌浆蛋白（Sln）表达加剧心肌损伤。引人注目的是，用AP-1抑制剂T-5224靶向该轴可有效提高阿霉素诱导的心肌病小鼠的存活率并增强心脏功能。本研究提供了对导致心肌功能障碍的能量重编程的机制性见解，从而为通过直接调节G6P-AP-1-Sln轴治疗阿霉素诱导的心肌病的抗能量重编程疗法提供了概念验证。
