Lin Yu-Te, Lee Yi-Ju, Tseng Wen-Wei, Chen Zih-Hua, Hsieh Huai-Ching, Lin Ko-Hong, Su Jin-Yu, Wei An-Chi
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, ROC.
Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan, ROC.
NPJ Syst Biol Appl. 2025 Jul 1;11(1):67. doi: 10.1038/s41540-025-00545-7.
Doxorubicin (DOX), although effective in treating cancer, has significant cardiac side effects, which limit its clinical utility. In this study, we collected time-course transcriptomics and metabolomics data from the human cardiomyocyte cell line AC16, which we analyzed along with curated public transcriptomics data on DOX-induced toxicity. We developed a multiomics analysis workflow and a computational toolbox, pipeGEM, to integrate RNA-seq data with metabolic models, enabling the simulation of DOX-induced metabolic perturbations at a sample-specific level. Our results revealed that DOX affected mitochondrial damage and mitochondria-to-nucleus retrograde signaling, potentially contributing to the observed cellular enlargement, senescence and metabolic shift. Cardiac cells that survived DOX treatment presented elevated glycolysis, increased pentose phosphate pathway activity, an altered TCA cycle, and modified glutathione and fatty acid metabolism. These findings provide a comprehensive understanding of DOX-induced toxicity and its implications for cardiac hypertrophy, suggesting potential strategies to mitigate side effects while retaining the anticancer efficacy of DOX.
阿霉素（DOX）虽然在治疗癌症方面有效，但具有显著的心脏副作用，这限制了其临床应用。在本研究中，我们收集了人心肌细胞系AC16的时间进程转录组学和代谢组学数据，并将其与精心整理的关于DOX诱导毒性的公共转录组学数据一起进行分析。我们开发了一种多组学分析工作流程和一个计算工具箱pipeGEM，以将RNA测序数据与代谢模型整合，从而能够在样本特异性水平上模拟DOX诱导的代谢扰动。我们的结果表明，DOX影响线粒体损伤和线粒体到细胞核的逆行信号传导，这可能导致观察到的细胞肿大、衰老和代谢转变。在DOX治疗中存活下来的心脏细胞表现出糖酵解升高、磷酸戊糖途径活性增加、三羧酸循环改变以及谷胱甘肽和脂肪酸代谢改变。这些发现为DOX诱导的毒性及其对心脏肥大的影响提供了全面的理解，为在保留DOX抗癌疗效的同时减轻副作用提供了潜在策略。
