Network modeling predicts how DYRK1A inhibition promotes cardiomyocyte cycling after ischemia/reperfusion injury
5 affiliations
- 1Department of Pharmacology
- 2Department of Medicine
- 3Department of Biomedical Engineering, and
- 4Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
- 5Perha Pharmaceuticals, Roscoff, France.
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 reentry 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 reentry. 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 inhibitors of DYRK1A is mediated by the induction of cycling CMs.
Related
- RBFOX2 Autoregulation Promotes Cardiomyocyte Transcriptome Maturation and Differentiation
- lncRNA Lockd promotes cardiomyocyte proliferation via Eno1/beta-catenin/Myc axis
- Cardiomyocyte-specific deletion of thioredoxin promotes myocardial injury, infarction and mitochondrial dysfunction: translocation of cytosolic thioredoxin into mitochondria rescue myocardial dysfunction by restoration of cardiac mitochondrial structure and function.
- Caloric Restriction Promotes Ischemia/Reperfusion Cardioprotection Through Increased Mitochondrial Na+/Ca2+ Exchange
- Sphingolipid-Driven Lipotoxicity Promotes Calcific Aortic Valve Disease Through ER-Stress-NF-κB-EndMT Signaling and Is Therapeutically Targetable Through Serine Palmitoyltransferase Inhibition
BibTeX
@article{murillo2026network,
title = {{Network modeling predicts how DYRK1A inhibition promotes cardiomyocyte cycling after ischemia/reperfusion injury}},
author = {Bryce C. Murillo and Alexander Young and Kaitlyn L. Wintruba and Alexander J. Eichert and Klara Siejda and Dennon Hoernig and Leigh A. Bradley and Bryana N. Harris and Catherine Zhao and Michelle Wu and Emmanuel Deau and Mattias F. Lindberg and Laurent Meijer and Jeffrey J. Saucerman and Matthew J. Wolf},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.200429},
url = {https://doi.org/10.1172/jci.insight.200429},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Network modeling predicts how DYRK1A inhibition promotes cardiomyocyte cycling after ischemia/reperfusion injury
AU - Bryce C. Murillo
AU - Alexander Young
AU - Kaitlyn L. Wintruba
AU - Alexander J. Eichert
AU - Klara Siejda
AU - Dennon Hoernig
AU - Leigh A. Bradley
AU - Bryana N. Harris
AU - Catherine Zhao
AU - Michelle Wu
AU - Emmanuel Deau
AU - Mattias F. Lindberg
AU - Laurent Meijer
AU - Jeffrey J. Saucerman
AU - Matthew J. Wolf
PY - 2026
DA - 2026/09/17
JO - JCI Insight
DO - 10.1172/jci.insight.200429
UR - https://doi.org/10.1172/jci.insight.200429
AB - 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 reentry 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 reentry. 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 inhibitors of DYRK1A is mediated by the induction of cycling CMs.
SN - 2379-3708
ER -