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ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/jci.insight.200429

Network modeling predicts how DYRK1A inhibition promotes cardiomyocyte cycling after ischemic/reperfusion injury

Bryce C. Murillo,1 Alexander Young,2 Kaitlyn L. Wintruba,3 Alexander J. Eichert,4 Klara Siejda,1 Dennon Hoernig,1 Leigh A. Bradley,1 Bryana N. Harris,3 Catherine Zhao,3 MIchelle Wu,3 Emmanuel Deau,5 Mattias F. Lindberg,5 Laurent Meijer,5 Jeffrey J. Saucerman,3 and Matthew J. Wolf1

1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

Find articles by Murillo, B. in: PubMed | Google Scholar

1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

Find articles by Zhao, C. in: PubMed | Google Scholar

1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

Find articles by Wu, M. in: PubMed | Google Scholar

1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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1Department of Pharmacology, University of Virginia, Charlottesville, United States of America

2Department of Medicine, University of Virginia, Charlottesville, United States of America

3Department of Biomedical Engineering, University of Virginia, Charlottesville, United States of America

4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States of America

5Perha Pharmaceuticals, Roscoff, France

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Published September 17, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.200429.
Copyright © 2026, Murillo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 17, 2026 - Version history
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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.

Graphical Abstract
graphical abstract
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Version history
  • Version 1 (September 17, 2026): In-Press Preview
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