Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy
Abstract 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 p...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | npj Systems Biology and Applications |
| Online Access: | https://doi.org/10.1038/s41540-025-00545-7 |
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| author | Yu-Te Lin Yi-Ju Lee Wen-Wei Tseng Zih-Hua Chen Huai-Ching Hsieh Ko-Hong Lin Jin-Yu Su An-Chi Wei |
| author_facet | Yu-Te Lin Yi-Ju Lee Wen-Wei Tseng Zih-Hua Chen Huai-Ching Hsieh Ko-Hong Lin Jin-Yu Su An-Chi Wei |
| author_sort | Yu-Te Lin |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-00e0b67aa8fa4e7d9a26c5f5898f07ac |
| institution | Kabale University |
| issn | 2056-7189 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Systems Biology and Applications |
| spelling | doaj-art-00e0b67aa8fa4e7d9a26c5f5898f07ac2025-08-20T03:45:31ZengNature Portfolionpj Systems Biology and Applications2056-71892025-07-0111112510.1038/s41540-025-00545-7Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophyYu-Te Lin0Yi-Ju Lee1Wen-Wei Tseng2Zih-Hua Chen3Huai-Ching Hsieh4Ko-Hong Lin5Jin-Yu Su6An-Chi Wei7Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan UniversityGraduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan UniversityGraduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan UniversityDepartment of Electrical Engineering, National Taiwan UniversityDepartment of Electrical Engineering, National Taiwan UniversityDepartment of Electrical Engineering, National Taiwan UniversityGraduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan UniversityGraduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan UniversityAbstract 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.https://doi.org/10.1038/s41540-025-00545-7 |
| spellingShingle | Yu-Te Lin Yi-Ju Lee Wen-Wei Tseng Zih-Hua Chen Huai-Ching Hsieh Ko-Hong Lin Jin-Yu Su An-Chi Wei Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy npj Systems Biology and Applications |
| title | Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy |
| title_full | Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy |
| title_fullStr | Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy |
| title_full_unstemmed | Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy |
| title_short | Temporal analysis of doxorubicin-induced cardiac toxicity and hypertrophy |
| title_sort | temporal analysis of doxorubicin induced cardiac toxicity and hypertrophy |
| url | https://doi.org/10.1038/s41540-025-00545-7 |
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