Abstract
Promoting cardiomyocyte proliferation is a highly promising strategy to repair the damaged myocardium and treat myocardial infarction (MI). DNA damage is a key factor leading to cell cycle arrest in cardiomyocytes, and DNA repair is required to relieve the restriction of proliferation. However, the potential of natural small-molecule compounds to enhance DNA repair and proliferation in cardiomyocytes has not been fully explored. Through screening of natural products, we found imperatorin could stimulate cardiomyocyte DNA repair and proliferation both in vitro and in vivo, which resulted in a significant improvement in cardiac function. By virtual prediction of pharmacological targets, we found that the target protein of imperatorin was the DNA repair protein tyrosyl-DNA phosphodiesterase 1 (TDP1). In terms of mechanism, imperatorin enhanced the phosphorylation of TDP1 at serine 81 by facilitating the proximity-mediated interaction between TDP1 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Collectively, these findings suggest that imperatorin is a promising lead for the development of cardiac regeneration agents, and TDP1 is a hitherto unrecognized potential therapeutic target for MI treatment.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (82200307, 82070362), by a grant from the National Key Research and Development Program of China (2022YFC3601305), and by grants from Jilin Province Special Project of Medical and Health Talents (JLSWSRCZX2023-9, JLSCZD2019-003). Illustration items in the figures were created with BioRender.com.
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Wenbin Fu: conceptualization, funding acquisition, investigation, data curation, project administration, formal analysis, and writing—original draft. Lulu Hou: data curation, methodology, project administration, and formal analysis. Xinyu Yang: investigation and software. Jingyue Wang: investigation and methodology. Jingyu Jin: investigation and methodology. Qian Tong: conceptualization, funding acquisition, supervision, and writing—review & editing.
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Fu, W., Hou, L., Yang, X. et al. Targeting TDP1 phosphorylation by the natural product imperatorin promotes DNA repair and cardiac regeneration. Commun Biol (2025). https://doi.org/10.1038/s42003-025-09429-2
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DOI: https://doi.org/10.1038/s42003-025-09429-2
