Novel Circular RNA circEZH2 Shows Promise in Preventing Endothelial Cell Aging and Atherosclerosis
Researchers have identified a circular RNA called circEZH2 that, when modified by a chemical tag known as m6A, protects endothelial cells from senescence and suppresses atherosclerosis progression in mice. The molecule works by stabilizing a protein called ZNF326 through a deubiquitination pathway, and its levels are reduced in aged arterial tissue and advanced atherosclerotic plaques. The findings suggest circEZH2 could be a potential therapeutic target for age-related cardiovascular disease.
A preprint study posted to bioRxiv reports the discovery of circEZH2, a circular RNA that carries an N6-methyladenosine (m6A) chemical modification and plays a protective role against endothelial cell senescence and atherosclerosis. The researchers used circRNA expression profiling and m6A-circRNA microarrays to screen endothelial cells and mouse aortic tissue, finding that circEZH2 levels decline in aged aortic intima and advanced atherosclerotic plaques in both mice and humans. Mechanistically, the m6A reader protein IGF2BP2 stabilizes circEZH2, which in turn acts as a molecular scaffold to promote USP37-mediated deubiquitination of ZNF326, preventing its degradation. In cell culture experiments, overexpression of circEZH2 reduced markers of senescence, lowered p53/p21 levels, and improved angiogenic activity, while knockdown had the opposite effects. In vivo, endothelial cell-specific overexpression of circEZH2 delayed senescence and slowed atherosclerosis progression in mice, and these benefits were reversed when ZNF326 was specifically knocked down in endothelial cells. The authors conclude that the m6A–circEZH2–USP37–ZNF326 axis represents a novel regulatory pathway in vascular aging and a candidate target for therapeutic intervention in atherosclerosis.
What's missing
As a preprint, this study has not yet undergone formal peer review, so its findings should be interpreted with caution. The study does not clarify whether circEZH2 overexpression produces any off-target effects or toxicity in vivo, nor does it address how circEZH2 might be delivered therapeutically in humans. The clinical relevance of the observed reduction in circEZH2 in human plaques is correlational, and causality in humans remains unestablished.
What different sources said
- bioRxivCenter
M6A-modified circEZH2 Protects Endothelial Cells from Senescence and Suppresses Atherosclerosis by Stabilizing ZNF326
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