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Researchers at the Department of Pharmacology and Toxicology at the University Medical Center Göttingen (UMG) have discovered a key genetic regulatory mechanism that becomes disrupted in heart failure. The findings were published in the renowned journal Signal Transduction and Targeted Therapy.
In heart failure the heart can no longer supply the body with enough blood. The condition often develops over many years, for example due to high blood pressure or other long-term strain on the heart muscle. At first, the heart tries to compensate for this extra workload by working harder, which causes it to enlarge. Over the long term, however, this adaptation leads to structural changes in the heart tissue, and the heart’s pumping function progressively deteriorates. Until now, it has been largely unclear which processes occur in the heart muscle during this process and can be specifically targeted for treatment.
A research team led by Prof. Dr. Laura Zelarayán, head of the “Developmental Pharmacology” research group at the Department of Pharmacology and Toxicology at the University Medical Center Göttingen (UMG), together with Dr. Eric Schoger, a former postdoctoral fellow, and Rosa Kim, a doctoral student, has discovered that the protein KLF15 plays a key regulatory role in the heart muscle and significantly loses activity in heart failure. At the same time, the researchers developed an approach to specifically reactivate this mechanism.
The findings were published in the renowned journal Signal Transduction and Targeted Therapy, part of the Nature Portfolio.
Original publication:
Schoger E. et al. Enhancing KLF15 activity in cardiomyocytes: a novel approach to prevent pathological reprogramming and fibrosis via nuclease-deficient dCas9VPR. Signal Transduction and Targeted Therapy (2026). DOI: https://doi.org/10.1038/s41392-026-02593-9
Genetic Switch
In a healthy heart, heart muscle cells function efficiently: they produce energy and contract rhythmically to pump blood throughout the body. Under sustained stress, however, this balance is disrupted. Certain genes are regulated differently than in a healthy state. Genes that are important for stable energy metabolism become less active. At the same time, programs are activated that are otherwise primarily known from the early developmental phase of the heart. This process is referred to as “pathological reprogramming” and contributes significantly to the deterioration of heart function.
The researchers in Göttingen were able to show that an important genetic “switch” plays a central role in this process: the transcription factor KLF15. Transcription factors are proteins that determine, within the cell nucleus, which genes are active and which are not. Using modern single-cell analyses, the researchers discovered that KLF15 activity decreases significantly in diseased heart muscle cells. This throws key genetic regulatory processes out of balance.
Precise Intervention Using Modern Genetic Engineering
Instead of artificially replacing the missing protein, the team took a different approach: Using a specialized variant of CRISPR technology, they specifically reactivated the body’s own KLF15 gene in heart muscle cells.
“This method, called CRISPR activation, does not alter the genetic material. Rather, it ensures that a natural gene switch is turned back on appropriately,” says Prof. Zelarayán, the study’s senior author.
In an animal model in which the heart was under constant strain, a clear protective effect was observed. Animals with reactivated KLF15 developed less severe cardiac enlargement, their pumping function remained more stable, and they survived longer than untreated control animals. The approach demonstrates that cardiac function can be stabilized through the targeted activation of the body’s own protective mechanisms.
Less Scarring in the Heart
“The effect is not limited to the heart muscle cells themselves. Connective tissue cells in the heart, known as fibroblasts, also respond positively,” says Prof. Zelarayán. Fibroblasts play a key role in the formation of scar tissue, which further impairs heart function. Reactivation of KLF15 led to increased production of a protective signaling protein called AZGP1. This protein inhibits the activation of fibroblasts and can thus reduce the formation of pathological scar tissue in the heart.
Additional studies on human heart tissue confirmed the significance of the findings. In samples from patients with various forms of heart muscle disease, KLF15 levels were significantly reduced. The study thus demonstrates for the first time that a disrupted genetic regulatory mechanism in the heart can be specifically normalized — with positive effects on the organ’s structure and function.
“In the long term, this approach could open up new perspectives for the treatment of heart failure and could also be applied to other molecular targets, particularly in diseases that are not caused by individual genetic mutations but by the dysregulation of entire genetic programs,” says Prof. Zelarayán.
Prof. Dr. Laura Zelarayán, Department of Pharmacology und Toxicology, Phone +49 551 / 39-68186, laura.zelarayan@med.uni-goettingen.de
Schoger E. et al. Enhancing KLF15 activity in cardiomyocytes: a novel approach to prevent pathological reprogramming and fibrosis via nuclease-deficient dCas9VPR. Signal Transduction and Targeted Therapy (2026). DOI: https://doi.org/10.1038/s41392-026-02593-9
Prof. Laura Zelarayán, head of the “Developmental Pharmacology” research group at the Department of ...
Copyright: umg/frank stefan kimmel, umg/samer al mhethawi, private
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