The adult human heart is a reliable and resilient engine fueling our everyday lives while also being responsive enough to supercharge a Usain Bolt sprint or sustain a three-week bike race in the French Alps and Pyrenees.
This marvel of biological machinery lacks an internal mechanic, however, as it is unable to repair itself after being injured by a heart attack. Researchers have shown that the mammalian heart’s self-repair system isn’t completely absent. Neonatal mouse hearts can regenerate for up to a week after birth.
Beyond that early window, are the heart’s fix-it powers lost for good? Or do they linger, dormant, able to be roused by the proper signal?
Scientists at Sanford Burnham Prebys Medical Discovery Institute and their collaborators across the U.S. published findings September 28, 2026, in Nature Cardiovascular Research detailing how a treatment enhances regeneration and cardiac function in mice. Changing how heart cells produce energy triggers coordinated changes in gene regulation across multiple cell types, promoting regeneration and improving recovery after a heart attack.
Previously, the research team had found that blocking an enzyme called succinate dehydrogenase worked to flip a metabolic switch in adult heart cells in mice. Resetting their metabolism to mimic how they produced energy in the neonatal stage prompted heart muscle cells to proliferate and promoted regeneration.
“Normally, mice lose the ability to regenerate their hearts just like humans and other mammals,” said senior and corresponding author Ahmed Mahmoud, PhD , interim director and associate professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys.
“After our treatment, we observed cardiac cells proliferating once again along with the formation of new blood vessels and a reduction in scar tissue that normally follows a heart attack.”
More research was needed to better understand what changes were happening within heart cells to reawaken their quiescent regenerative abilities. The investigators began by using sequencing techniques to measure changes in gene expression and DNA accessibility in mice treated with a metabolite called malonate that blocks succinate dehydrogenase.
“We found that regions of DNA associated with pro-regenerative and cell cycle genes became more accessible in heart muscle cells, making it easier for the cell to activate these programs,” said co-first author Yi Fan, PhD, a postdoctoral associate in the Mahmoud lab at Sanford Burnham Prebys.
“The other most pronounced change was a suppression of scar-forming programs in connective tissue cells known as cardiac fibroblasts.”
These observations led the research team to focus additional experiments on these cell types. They wanted to see the effects of blocking succinate dehydrogenase in each cell type in isolation, which isn’t possible with a malonate injection that circulates throughout the heart and vascular system. Instead, the scientists ran tests in two newly developed mouse models genetically altered to disrupt succinate dehydrogenase activity in either their heart’s muscle or connective tissue cells.
The results revealed an important distinction. Blocking succinate dehydrogenase specifically in cardiomyocytes produced a transient increase in their proliferation, but this alone was not sufficient to improve heart function after a heart attack. In contrast, blocking the enzyme in cardiac fibroblasts suppressed their activation and reduced scar formation, resulting in improved cardiac function.
The findings also highlighted the importance of timing. Unlike sustained genetic disruption of succinate dehydrogenase activity, malonate temporarily inhibits the enzyme, potentially allowing heart cells to enter a regenerative state and then return to the mature metabolic state needed for normal cardiac function.
“We were somewhat cardiomyocyte-centric in our initial hypotheses,” said co-first author Dakota Nuttall, a PhD student in the Mahmoud lab. “The results demonstrated the importance of both cell types for successful regeneration and recovery.”
“It is a multicellular effect that's driving regeneration, which is something we couldn't fully appreciate until we isolated the effects of metabolic reprogramming in different cell types,” said Mahmoud.
In a final round of experiments, the research team returned to treating mice with malonate to see how the therapy changed the way DNA was packaged and regulated in heart cells. DNA is wound up like thread on biological spools called histones, and adjustments that tighten or loosen how it is coiled in certain areas can close off or open up nearby genes.
“In cardiomyocytes, we could see an activating histone modification associated with genes important for regeneration being turned on,” said Fan.
“And, likewise, in cardiac fibroblasts, we could see changes in histone marks that turned down genes involved in scarring or fibrosis,” said Nuttall.
Now, the scientists have a clearer picture showing how their treatment strategy promotes regeneration in mouse models, providing further evidence for advancing this potential therapeutic strategy.
“One of the most exciting aspects of this work is that metabolic reprogramming appears to reawaken several features of the regenerative response normally seen in the neonatal heart,” said Mahmoud. “Rather than targeting a single regenerative pathway, we are changing the metabolic state of the tissue in a way that coordinates responses across multiple cell types.”
“Our long-term goal is to translate this concept toward clinical testing and ultimately develop a therapy for the more than 800,000 people in the U.S. who experience a heart attack each year.”
Additional authors include:
The study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Wisconsin Partnership Program at the University of Wisconsin School of Medicine and Public Health and Penn Cardiovascular Institute at the University of Pennsylvania Perelman School of Medicine.
The study’s DOI is 10.1038/s44161-026-00881-9 .
Nature Cardiovascular Research
Experimental study
Animals
A metabolic–epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition
28-Sep-2026
Ahmed Mahmoud is co-founder of and owns shares in Mount Therapeutics, Inc. Mahmoud and Jiyoung Bae are co-inventors on US Patent No. 11,813,239 (issued; continuation pending), which covers the use of succinate dehydrogenase inhibition to promote cardiac regeneration, including the pharmacological approach investigated in this study. The remaining authors declare no competing interests.