The enzyme in question is succinate dehydrogenase, or SDH, a mitochondrial complex that sits at the junction of two of the cell’s most important energy systems: the tricarboxylic acid cycle and the electron transport chain. SDH has long been studied in the context of ischemia-reperfusion injury, where the drug malonate can reduce the damaging accumulation of succinate and limit mitochondrial reactive oxygen species during reperfusion. It has also drawn attention in cancer biology, because mutations in SDH genes drive dramatic metabolic reprogramming in certain tumors. The research team hypothesized that transiently inhibiting SDH after a myocardial infarction could push the adult heart back toward a more regenerative, fetal-like metabolic state.

Their earlier work had already shown promise: transient malonate treatment after infarction increased cardiomyocyte proliferation and angiogenesis, reduced fibrosis, and improved cardiac function in adult mice. Importantly, treatment delayed until seven days after injury still restored function, suggesting the effect was true regeneration rather than mere acute cardioprotection. What remained unclear was how this transient metabolic intervention rewired the heart at the level of genes and chromatin. To find out, the team deployed an unusually comprehensive toolkit: single-nucleus RNA sequencing, single-nucleus ATAC-seq to map chromatin accessibility, targeted metabolomics, and cell-type-specific genetic deletion of Sdhb, the gene encoding a core SDH subunit.

The multiomic analysis of mouse hearts treated with malonate for fourteen days after infarction revealed that nearly every major cardiac cell type, including cardiomyocytes, cardiac fibroblasts, endothelial cells, mural cells and myeloid cells, formed treatment-specific subclusters with distinct transcriptional and epigenetic profiles. In untreated infarcted hearts, profibrotic and extracellular matrix programs dominated, most strongly in fibroblasts. In malonate-treated hearts, the picture shifted toward metabolic, chromatin remodeling and proregenerative programs, particularly within cardiomyocytes. A specific cardiomyocyte subcluster emerging after treatment expressed genes associated with cell-cycle progression, cardiac development and neonatal-like regeneration, including Ccnd3, Lrrc10, Tcap, Cited2, Lifr and Ezh1, alongside activation of PI3K-AKT and AMPK signaling pathways known to support cardioprotective and proregenerative responses.

Chromatin analysis reinforced the story. The regenerative cardiomyocyte subcluster showed increased accessibility at the cell-cycle gene Ccnd3 and the metabolic regulator Pdk4, and enriched accessibility of motifs for the MEF2 family of transcription factors, which are central to cardiac development and regeneration, as well as FOXK1 and FOXK2, which promote cardiomyocyte proliferation. Fibroblasts told the complementary tale: in untreated infarcts, a subcluster expressed profibrotic genes such as Postn, Fn1, Runx1 and Acta2, marking activated myofibroblasts. After malonate treatment, that myofibroblast population shrank dramatically, and fibroblasts instead expressed reparative WNT/BMP signaling genes like Egr1 and Notch1 along with chromatin remodelers Kdm6b and Kdm7a, with chromatin accessibility mirroring the transcriptional shift.

The genetic models then dissected which cells matter most, and the results were strikingly asymmetric. Deleting Sdhb specifically in cardiomyocytes triggered a transient burst of proliferation, with roughly one hundred-fold more Ki67-positive cardiomyocytes and about threefold increases in mitotic and cytokinesis markers two weeks after induction. Yet this hyperplasia faded by four weeks, and although sustained deletion after infarction increased cumulative proliferation and reduced scar area, serial echocardiography showed progressive deterioration of systolic function rather than recovery. All cardiomyocyte-specific knockout mice eventually died by around eleven weeks after induction, whether or not they had suffered an infarction, underscoring that permanent SDH loss is ultimately harmful even as it briefly revives proliferation.

Metabolomics explained why the proliferative window is so narrow. Two weeks after Sdhb deletion, oxidative TCA cycle intermediates such as succinate, fumarate and malate were depleted, while reductive metabolism products like proline and ornithine accumulated, and amino acid pools were broadly remodeled with elevated 3-methylhistidine, a marker of myofibrillar protein breakdown. Electron microscopy revealed smaller, disorganized mitochondria with fewer cristae and disrupted sarcomeres, hallmarks of a less mature cellular state. Crucially, global levels of the histone marks H3K4me3 and H3K27me3, which mark active and repressive chromatin respectively, were reduced during the proliferative phase, directly linking mitochondrial metabolism to epigenetic state. In human induced pluripotent stem cell-derived cardiomyocytes, malonate, succinate and malate each boosted proliferation, while fumarate proved toxic, pinpointing specific TCA intermediates as candidate proproliferative signals.

Myofibroblast-specific Sdhb deletion produced an entirely different and arguably more therapeutically relevant outcome. When the researchers deleted Sdhb in activated fibroblasts using a Postn-MerCreMer system, the animals showed robust suppression of myofibroblast activation, with reduced POSTN, COL3A1 and alpha-SMA staining at one and two weeks after infarction, smaller scars, and significantly improved ejection fraction and fractional shortening as early as one week after injury, sustained through four weeks. Notably, this functional benefit occurred without any increase in cardiomyocyte proliferation, and surviving myocardial area was unchanged early on, indicating the improvement stemmed from restraining fibrotic remodeling rather than protecting muscle. In cultured neonatal cardiac fibroblasts, malonate suppressed TGF-beta1-induced activation, proliferation and migration while reducing H3K4me3 and COL3A1 protein, suggesting SDH inhibition silences profibrotic genes through epigenetic repression.

CUT&RUN profiling of purified cardiomyocytes and fibroblasts tied the whole mechanism together. In malonate-treated infarcted hearts, differentially expressed genes showed increased H3K4me3 and decreased H3K27me3 relative to matched background genes, and thousands of histone-mark-associated loci differed between treatment groups. H3K4me3 sites enriched after malonate mapped to genes such as Lrrc10, Lifr, Pdk4 and Tecrl and to pathways governing cardiac muscle development and contractile function, while reduced H3K27me3 mapped to cardiac morphogenesis and tissue remodeling programs. The authors propose a biphasic model: transient suppression of oxidative metabolism permits cardiomyocyte cell-cycle reentry and chromatin remodeling toward a neonatal-like state, and subsequent restoration of SDH activity allows redifferentiation and maturation. Permanent genetic deletion, by contrast, blocks that recovery phase and may even constrain pyrimidine biosynthesis through succinate-mediated effects on aspartate metabolism, imposing replication stress that transient pharmacology avoids.

The broader lesson is that heart regeneration is not a single-cell phenomenon. Cardiomyocyte proliferation alone, as the knockout experiments demonstrate, cannot restore function; the antifibrotic reprogramming of fibroblasts is equally essential, and the two effects must be coordinated in time. Transient, reversible, multicellular SDH inhibition achieves what permanent genetic deletion in any one cell type cannot. The work also leaves open questions, including the roles of endothelial, mural and myeloid cells, the earliest temporal events after injury, and the long-term safety of metabolic intervention with respect to cardiomyocyte maturation and arrhythmogenic risk. Still, by identifying SDH as a metabolic-epigenetic hub linking mitochondrial function to chromatin state across the injured heart, the study establishes metabolic-epigenetic crosstalk as a credible therapeutic axis for coaxing the adult myocardium back into a developmental program it abandoned long ago.

Subject of Research: Metabolic and epigenetic mechanisms of cardiac regeneration following succinate dehydrogenase inhibition after myocardial infarction

Article Title: A metabolic–epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition

Article 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. https://doi.org/10.1038/s44161-026-00881-9

Image Credits: AI Generated

DOI: 10.1038/s44161-026-00881-9

Keywords: cardiac regeneration, succinate dehydrogenase, malonate, myocardial infarction, cardiomyocyte proliferation, fibrosis, epigenetics, H3K4me3, H3K27me3, metabolism, single-nucleus sequencing, myofibroblasts

Lymphatic vessels are best known as the body’s drainage network, collecting interstitial fluid, ferrying immune cells, and absorbing dietary fats. In most textbook accounts, they are supporting infrastructure rather than active participants in organ construction. The new study, published in the journal Genes & Development, challenges that view. Led by senior author Guillermo Oliver, the Thomas D. Spies Professor of Lymphatic Metabolism at Northwestern, the research demonstrates that cardiac lymphatic vessels send molecular signals to multiple types of heart cells, actively shaping how the growing heart regulates its own size.

The work builds directly on an earlier discovery from the Oliver laboratory, which showed that lymphatic vessels in the heart secrete a protein called Reelin. Reelin is famous in neuroscience, where it orchestrates the layered migration of neurons in the developing brain, but its role in the heart was a surprise. In that earlier work, the team found that Reelin promotes cardiac growth by stimulating the proliferation of cardiomyocytes, the contractile muscle cells that make up the bulk of the heart. When cardiomyocytes divide during embryonic development, the heart enlarges; when they stop dividing, as happens shortly after birth in mammals, that growth largely ceases.

The new study reveals that Reelin’s influence extends well beyond heart muscle. Using single-cell RNA sequencing, a technique that profiles gene expression in thousands of individual cells at once, combined with genetically engineered mouse models in which lymphatic-derived Reelin was eliminated, the researchers mapped a signaling pathway that connects the cardiac lymphatics to the epicardium, the thin layer of tissue that envelops the heart’s outer surface. The epicardium is far more than a protective membrane. During development it serves as a source of fibroblasts, coronary vascular cells, and growth factors, making it essential for normal cardiac morphogenesis.

What the team observed in mice lacking lymphatic-derived Reelin was striking. These hearts developed significant defects in the epicardium and lost specific populations of fibroblasts, the cells that build and maintain the heart’s structural scaffold. The investigators also documented a reduction in the number of epicardial cells expressing two critical cardiac factors: WT1, a transcription factor with well-established roles in epicardial biology and cardiac progenitor function, and insulin-like growth factor-1, or IGF-1, a potent growth factor that drives tissue expansion. In other words, removing a single lymphatic signal disrupted an entire regulatory network governing cardiac growth.

“We recently identified the cardiac lymphatic vasculature as an unexpected regulator of heart size during embryonic development,” Oliver said. “Here, by combining single-cell RNA sequencing with loss-of-function mouse models, we uncover another novel and unexpected critical regulatory network also participating in this process.” According to Oliver, the findings show that Reelin is not merely a muscle-cell proliferation signal but is essential for the maintenance and expansion of other cardiac cell types, including the epicardium and fibroblasts, and for sustaining the expression of WT1 and IGF-1, which together are responsible for the growth of the heart.

To test whether the mechanism holds in human tissue, the researchers turned to laboratory-grown human epicardioids, three-dimensional organoids that recapitulate key features of the developing heart’s outer lining. These mini-hearts, cultivated from human cells, allowed the team to probe Reelin’s effects in a controlled system that is more representative of human biology than mouse tissue alone. When the organoids were treated with Reelin protein, the expression of multiple epicardial markers increased, indicating that the protein promoted epicardial cell fate. This result supports the idea that Reelin directly influences epicardial maintenance during development and can even induce epicardial characteristics in the adult heart.

That last point carries significant implications for regenerative medicine. The mammalian heart loses most of its regenerative ability shortly after birth, and the epicardium, so active during embryogenesis, becomes largely dormant in the adult. Yet this dormant layer retains latent developmental programs that can be partially reawakened after injury, such as a heart attack, when the epicardium thickens and re-expresses genes like WT1. The Northwestern findings suggest that the beneficial effects of lymphatic vessels during adult cardiac injury may be partly mediated by Reelin reactivating the dormant epicardium, potentially leading to more efficient repair. If researchers could one day harness or mimic that signal, they might enhance the heart’s limited self-repair capacity after a myocardial infarction, the leading cause of death worldwide.

Timing appears to be everything. Oliver noted that Reelin expression in cardiac lymphatics declines progressively after birth and becomes nearly undetectable by day seven of life in mice. That postnatal decrease coincides precisely with the window in which newborn mice lose their ability to regenerate heart tissue, a phenomenon first described in landmark studies showing that a one-day-old mouse can fully repair its heart after surgical injury, while a seven-day-old mouse cannot. “This postnatal decrease coincides with the cessation of cardiac regeneration in newborn mice, suggesting that loss of Reelin may contribute to the arrest of these processes,” Oliver said. The correlation does not prove causation, but it provides a compelling lead for scientists trying to understand why the regenerative capacity of the heart switches off so early in life.

Beyond regeneration, the work may illuminate the origins of congenital heart defects, which affect roughly one percent of live births and often involve faults in the very cell types and signaling pathways the study identifies. If lymphatic-derived signals are required for proper epicardial maintenance, fibroblast development, and growth factor expression, then disruptions in cardiac lymphatic development could plausibly contribute to structural heart malformations, a hypothesis the authors suggest is worth investigating in future work.

Oliver and his colleagues have also proposed a broader and provocative conceptual model: that lymphatic vessels may function as organ-wide monitoring systems that help determine when growth is complete. As lymphatics grow into a developing organ, they are uniquely positioned to sample functional features of the tissue around them, including interstitial fluid pressure, the accumulation of metabolic waste, and tissue stiffness, all of which change as an organ matures. “What we propose is that it’s possible that lymphatics function as organ-level quality control systems,” Oliver said. In this view, the vessels continuously assess the organ’s condition and relay instructions: keep growing, keep proliferating, until the tissue reaches an appropriate state, and then stop.

If that model proves correct across organ systems, it would reframe the lymphatic vasculature from a passive drainage network into an active, instructive component of organogenesis, with Reelin as one of its molecular messengers. It would also connect two fields that have historically developed in parallel, lymphatic biology and cardiac developmental biology, around a shared question of size control. The technical achievements underpinning the study, from single-cell transcriptomics that resolved the cross-talk between lymphatic endothelial cells, epicardial cells, and fibroblasts, to the generation of human epicardioids that allowed direct functional testing, illustrate how modern tools are enabling biologists to dissect these multicellular conversations with unprecedented precision.

Much remains to be determined. The study was conducted in mice and in lab-grown organoids, and translating the findings to human therapy will require years of additional research, including work to establish whether Reelin signaling can be safely and effectively modulated in the injured adult heart. Still, the central message is clear and conceptually striking: the heart’s blueprint for growth is not written in muscle cells alone. It is co-authored by the lymphatic vessels threading through the organ, which whisper instructions to the epicardium, sustain the fibroblasts that build its framework, and keep the growth factors flowing until the job is done. Understanding that conversation, the Northwestern team argues, could ultimately give science new insight into how the heart responds to and repairs itself after a heart attack, turning a developmental curiosity into a potential therapeutic frontier.

Subject of Research: The role of lymphatic-derived Reelin signaling in regulating epicardial maintenance and cardiac growth during heart development

Article Title: Study reveals a new way the developing heart controls its growth

Article References: Study reveals a new way the developing heart controls its growth. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cardiac lymphatics, Reelin, epicardium, heart development, cardiomyocyte proliferation, fibroblasts, WT1, IGF-1, organoids, regeneration, congenital heart defects, single-cell RNA sequencing