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circHIPK3 Sustains Ribosome Biogenesis and Protects Against Cardiac Aging by Stabilizing Ncl mRNA and Supporting its
Huiling Zhang1, Tonggan Lu1, Xinlan Lv1
1Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China.
Aging and Disease
|May 18, 2026
Summary
Circular RNA HIPK3 (circHIPK3) protects against cardiac aging by stabilizing Nucleolin (Ncl) and supporting ribosome biogenesis. This novel circHIPK3-Ncl axis offers therapeutic potential for age-related cardiovascular dysfunction.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Aging Biology
Background:
- Cardiac aging involves complex molecular mechanisms.
- Circular RNAs (circRNAs) are emerging as key regulators in biological processes.
- Nucleolin (Ncl) plays a critical role in ribosome biogenesis and cellular function.
Purpose of the Study:
- To elucidate the role of circHIPK3 in cardiac aging.
- To identify the molecular targets and pathways regulated by circHIPK3.
- To explore circHIPK3 as a potential therapeutic target for cardiovascular aging.
Main Methods:
- Generated cardiomyocyte-specific circHIPK3 knockout (CKO) mice.
- Investigated circHIPK3 binding to Ncl mRNA using molecular assays.
- Assessed ribosome biogenesis, Ncl protein levels, and cardiac function in vivo and in vitro.
- Utilized circHIPK3 overexpression models.
Main Results:
- circHIPK3 expression decreases with age in mouse hearts.
- circHIPK3 deficiency in CKO mice led to cardiac aging phenotypes, dysfunction, hypertrophy, and fibrosis.
- circHIPK3 stabilizes Ncl mRNA, enhancing Ncl protein levels and Ncl-mediated liquid-liquid phase separation (LLPS) for ribosome biogenesis.
- circHIPK3 deficiency impaired ribosome production and exacerbated aging phenotypes.
- circHIPK3 overexpression rescued these defects and alleviated cardiac aging.
Conclusions:
- Identified a novel "circHIPK3-Ncl-ribosome biogenesis" axis regulating cardiac aging.
- circHIPK3 protects against cardiac aging via post-transcriptional and biophysical regulation of Ncl.
- circHIPK3 is a potential biomarker and therapeutic candidate for age-related cardiovascular dysfunction.
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