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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
PubMed

Insights

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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