Targeting TDP1 phosphorylation by the natural product imperatorin promotes DNA repair and cardiac regeneration

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.