Targeting Circular RNA to Reduce Inflammatory Fibrosis and Heart Failure Progression

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Summary of  European Heart Journal https://doi.org/10.1093/eurheartj/ehaf1116  
Dr. Mira Jung  et al.

Points

Researchers identified a novel circular RNA called circHIPK2 that acts as a molecular switch to promote inflammatory macrophage activity and heart muscle scarring following a major myocardial infarction.
The study found that disabling this specific genetic switch reduces the formation of stress granules in immune cells which significantly slows down the development of pathological cardiac fibrosis and stiffening.
Using living human heart slices and advanced imaging techniques the team demonstrated that silencing circHIPK2 improves overall cardiac performance and promotes more effective healing in failing heart tissue.
Circular RNAs are ideal targets for new drug therapies because they are highly stable within cells and have remained largely unchanged throughout human evolution across different biological systems.
This innovative approach shifting macrophages from inflammatory to reparative states represents a potential breakthrough in preventing chronic heart failure for the hundreds of thousands of patients suffering heart attacks.

Summary

This research evaluated the role of circHIPK2, a novel circular RNA, in modulating macrophage polarization following myocardial infarction. While macrophages are essential for removing dead tissue, their polarization toward the pro-inflammatory M1 phenotype often triggers an inflammatory cascade that contributes to pathological fibrosis and chronic heart failure. The study identified circHIPK2 as a key molecular switch that is upregulated in M1 macrophages after ischemic injury. By promoting the formation of stress granules, this circular RNA initiates a downstream signaling pathway that increases the deposition of connective tissue, leading to myocardial scarring and ventricular stiffening.

The investigators utilized a combination of cardiac ultrasound, positron emission tomography imaging, and living heart slices from human transplant patients to assess the impact of circHIPK2 inhibition. In model systems, the targeted elimination of this circular RNA in macrophages significantly reduced the inflammatory response and slowed the progression of cardiac fibrosis. These interventions resulted in a marked improvement in cardiac performance and global heart function. The study successfully translated these molecular findings into a clinically relevant context by deactivating the circHIPK2 switch in induced pluripotent stem cell-derived human macrophages, which subsequently promoted healing when introduced to failing human heart tissue.

The findings suggest that RNA-based therapies targeting circHIPK2 represent a promising therapeutic strategy for mitigating post-infarct cardiac remodeling. Because circular RNAs are species-conserved and highly stable within the family of non-coding RNAs, they serve as ideal pharmacological targets. By shifting the macrophage population away from a chronic M1 stress-granule-forming state and toward an M2 reparative phenotype, clinicians may be able to interrupt the transition from acute myocardial infarction to chronic cardiac insufficiency. This research underscores the potential for immunomodulatory RNA therapies to enhance the intrinsic regenerative capacity of the adult human heart

Link to the article: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaf1116/8471743?login=false#google_vignette

References

Jung, M., Schmidt, A., Sansonetti, M., Al Soodi, B., Thum, S., Pfanne, A., Just, A., Xiao, K., Huang, C.-K., Erschow, S., Ricke-Hoch, M., Oehlsen, L., Agyapong, W., Jansen, K., Blume, J., Büchler, G., Hilbold, E., Bär, C., Weber, N., … Thum, T. (2026). Macrophage-specific circular RNA circHIPK2, inflammation, and fibrosis after myocardial infarction. European Heart Journal, ehaf1116. https://doi.org/10.1093/eurheartj/ehaf1116