Transient Succinate Dehydrogenase Inhibition Promotes Cardiac Functional Recovery After Myocardial Infarction

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Data Quality: STRONG
Summary of  Nature Cardiovascular Research https://doi.org/10.1038/s44161-026-00881-9
Dr. Yi Fan et al.

Points

Researchers at Sanford Burnham Prebys discovered that transiently inhibiting the mitochondrial enzyme succinate dehydrogenase reawakens dormant regenerative capacity in adult mammalian hearts following myocardial infarction.
Multi-omic sequencing revealed that metabolic reprogramming via malonate alters histone modifications and chromatin accessibility across both heart muscle cells and connective tissue fibroblasts.
Isolated cardiomyocyte specific enzyme deletion increased cell proliferation but failed to restore functional recovery without concurrent attenuation of cardiac scar tissue formation.
Disruption of succinate dehydrogenase specifically within myofibroblasts suppressed fibroblast activation and reduced fibrosis resulting in significant functional improvements after heart muscle injury.
Findings establish that transient metabolic switches coordinate multicellular repair programs offering a promising therapeutic strategy for over eight hundred thousand annual heart attack patients.

Summary

This study evaluated the regenerative mechanisms of transient succinate dehydrogenase (SDH) inhibition in adult mammalian hearts following myocardial infarction. Published in Nature Cardiovascular Research by investigators at Sanford Burnham Prebys, the research examined how metabolic reprogramming via malonate or genetic Sdhb deletion alters epigenetic chromatin accessibility and cell proliferation across distinct cardiac cell types. The investigation sought to delineate cell-specific contributions to post-infarction tissue repair, targeting the more than 800,000 individuals in the United States who suffer a heart attack annually.

Using single-nucleus RNA sequencing, ATAC-seq, and CUT&RUN chromatin profiling, the study mapped transcriptional and epigenetic remodeling in cardiomyocytes and cardiac fibroblasts. Cardiomyocyte-specific Sdhb deletion promoted a transient increase in cardiomyocyte proliferation; however, this isolated response was insufficient to recover post-myocardial infarction cardiac function. In contrast, myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and reduced scar formation, driving significant functional recovery. Transient pharmacological inhibition with malonate successfully promoted reductive mitochondrial metabolism while modifying H3K4me3 and H3K27me3 histone marks across both cell lineages.

The authors conclude that transient SDH inhibition activates a coordinated, multicellular repair program rather than relying on a single regenerative pathway. By temporarily reawakening neonatal-like metabolic and chromatin states, transient malonate administration successfully balances cardiomyocyte proliferation with attenuated cardiac fibrosis. These findings demonstrate that cell-specific metabolic and epigenetic switch mechanisms are critical for restoring cardiac performance, supporting the translational advancement of transient SDH inhibition toward clinical trials.

Link to the article: https://www.nature.com/articles/s44161-026-00881-9

References

Fan, Y., Nuttall, D. J., Zhao, Y., Abbasian, D., Shoffler, C., Petucci, C., Paltzer, W. G., Chang, Y.-L., Marchant, J., Presas-Ramos, D., Atlass, K. P., Nemr, S. A., Bae, J., Ranade, S. S., Colas, A. R., Li, X., Martin, J. F., & Mahmoud, A. I. (2026). A metabolic–epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition. Nature Cardiovascular Research, 1–21. https://doi.org/10.1038/s44161-026-00881-9