Network Modeling Predicts How DYRK1A Inhibition Promotes Cardiomyocyte Cycling after Ischemic/Reperfusion Injury

Murillo, B. C.; Young, A.; Wintruba, K. L.; Eichert, A. J.; Siejda, K.; Hoenig, D.; Bradley, L. A.; Harris, B. N.; Zhao, C.; Wu, M.; Deau, E.; Lindberg, M. F.; Meijer, L.; Saucerman, J. J.; Wolf, M. J.

doi:10.1101/2025.08.19.671147

bioRxiv · 10.1101/2025.08.19.671147

Network Modeling Predicts How DYRK1A Inhibition Promotes Cardiomyocyte Cycling after Ischemic/Reperfusion Injury

Murillo, B. C.·Young, A.·Wintruba, K. L.·Eichert, A. J.·Siejda, K.·Hoenig, D.·Bradley, L. A.·Harris, B. N.·Zhao, C.·Wu, M.·Deau, E.·Lindberg, M. F.·Meijer, L.·Saucerman, J. J.·Wolf, M. J.

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Abstract

The adult mammalian heart has a limited ability to regenerate lost myocardium following myocardial infarction (MI), largely due to the poor proliferative capacity of cardiomyocytes (CMs). Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a known regulator of cell quiescence, though the mechanisms underlying its function remain unclear. Previous studies have shown that pharmacological inhibition of DYRK1A using harmine induces CM cell cycle re-entry after ischemia/reperfusion (I/R) MI. Here, we developed a computational network model of DYRK1A-mediated regulation of the cell cycle, which predicts how DYRK1A inhibition promotes CM re-entry. To validate these predictions, we tested selective DYRK1A inhibitors and observed robust induction of cell cycle activity in neonatal rat cardiomyocytes (NRCMs). Integrating our network model with bulk RNA-sequencing data from DYRK1A inhibitor-treated NRCMs, we identified E2F1 as a key transcriptional driver of cell cycle gene expression. Finally, we demonstrate that both pharmacological and post-developmental inhibition of DYRK1A enhances heart function and increases CM cycling following I/R MI. Our findings suggest that functional recovery induced by small molecule inhibitor of DYRK1A is mediated by the induction of cycling CMs. One Sentence SummaryInhibition of DYRK1A through LCTB-92 induces cardiomyocyte cycling and improved heart function in a mouse model of ischemic/reperfusion injury.

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Murillo, B. C., Young, A., Wintruba, K. L., Eichert, A. J., Siejda, K., Hoenig, D., Bradley, L. A., Harris, B. N., Zhao, C., Wu, M., Deau, E., Lindberg, M. F., Meijer, L., Saucerman, J. J., Wolf, M. J.. 2025-08-23. Network Modeling Predicts How DYRK1A Inhibition Promotes Cardiomyocyte Cycling after Ischemic/Reperfusion Injury. https://doi.org/10.1101/2025.08.19.671147

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