Their attention centered on a protein complex called the super elongation complex (SEC), which controls a crucial step in fast gene transcription. For many genes, transcription pauses shortly after it starts — a built-in brake. The SEC complex can release this pause, allowing genes to be activated very rapidly.

The study shows that this rapid-release process switches on precisely at the onset of the cells' pathological transformation. Tissue from atherosclerosis patients confirmed the link: SEC components were especially abundant in endothelial cells already showing signs of the transition.

"We were able to show that when endothelial cells undergo pathological changes, it is not only which genes are activated that matters, but also how quickly this cellular transcription takes place," Boeckel said. "This early phase of gene regulation offers a largely unexplored therapeutic target that is currently also gaining relevance in cancer therapy."

Slowing transformation in cells and tissue models

In human endothelial cells, the researchers inhibited the SEC complex with experimental compounds. This slowed the pathological transformation and allowed the cells to keep the functional properties needed to maintain the vascular barrier.

The reverse experiment strengthened the case. When the scientists boosted the activity of a key SEC component, endothelial cells developed disease-related characteristics even without any additional stimuli.

The effect also appeared in a more physiologically realistic setting. In cardiac organoids — three-dimensional models of heart tissue grown in the laboratory — SEC inhibition reduced both excessive collagen deposition and impaired heart muscle cell function.

Results in mice and human plaque samples

The most therapeutically relevant results came from an atherosclerosis model in mice. Treated animals showed a lower plaque burden, reduced macrophage infiltration (an indicator of inflammation, since macrophages are immune cells that accumulate in unstable plaques), and fewer pathological endothelial cells. Notably, SEC inhibition reduced vascular changes both preventively and therapeutically — that is, in mice with already established atherosclerosis.

Analyses of 1,048 sections of human plaques from the AtheroExpress biobank at Utrecht University in the Netherlands further confirmed the mechanism's importance.

"What is particularly exciting is that we were able to trace this mechanism from human vascular samples and molecular analyses through to functional models," Boeckel said. "Inhibiting RNA elongation not only reduced changes in individual cells, but also had a beneficial effect on characteristics of atherosclerotic plaques."

From lab bench toward the clinic — cautiously

The inhibitors used in this study remain experimental, and the findings are preliminary in terms of clinical application. However, the approach has a potential shortcut to relevance: compounds that slow gene transcription by targeting CDK9, one component of the SEC complex, are already undergoing clinical trials in cancer medicine. Further studies will need to establish whether this approach transfers to vascular diseases in humans.

Still, as the researchers note, the first steps toward a therapy for unstable plaques — the kind that cause heart attacks and strokes — have now been taken.

Reference: Karoline E. Kokot et al., "Targeting super elongation complex-driven RNA polymerase II elongation reduces plaque vulnerability," Signal Transduction and Targeted Therapy (2026). DOI: 10.1038/s41392-026-02962-4