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E3 Ubiquitin Ligase TRIM21 Exacerbates Pathological Cardiac Hypertrophy Through ASK1 K63-Linked Polyubiquitination

Hongjie Shi1,2, Jing Xie1, Sha Hu2

  • 1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|December 8, 2025
PubMed

Insights

Tripartite Motif Containing 21 (TRIM21) drives pathological cardiac hypertrophy by activating the ASK1-JNK/p38 MAPK pathway. Inhibiting this TRIM21-ASK1 axis offers a potential therapeutic strategy for heart disease.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Signaling

Background:

  • Pathological cardiac hypertrophy is a significant risk factor for severe cardiovascular outcomes like heart failure.
  • The intricate molecular mechanisms underlying cardiac hypertrophy are not fully elucidated.
  • Identifying novel molecular players is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of Tripartite Motif Containing 21 (TRIM21) in pathological cardiac hypertrophy.
  • To elucidate the molecular mechanisms by which TRIM21 influences cardiac hypertrophy.
  • To assess the therapeutic potential of targeting the TRIM21 pathway.

Main Methods:

  • Utilized mouse models of cardiac hypertrophy (transverse aortic constriction) and in vitro cell culture systems (phenylephrine-stimulated cardiomyocytes).
  • Performed TRIM21 knockdown and overexpression studies in vitro and in vivo.
  • Investigated protein-protein interactions and post-translational modifications, including polyubiquitination of ASK1.
  • Analyzed downstream signaling pathway activation (JNK/p38 MAPK) and employed pharmacological inhibition of ASK1.

Main Results:

  • TRIM21 expression was significantly upregulated in hypertrophic cardiac models.
  • TRIM21 knockdown attenuated cardiomyocyte hypertrophy, while overexpression exacerbated it.
  • TRIM21 directly interacted with ASK1, promoting its K63-linked polyubiquitination and subsequent activation.
  • Activation of JNK/p38 MAPK pathways was dependent on TRIM21 and ASK1.
  • Pharmacological inhibition of ASK1 abrogated the pro-hypertrophic effects of TRIM21.

Conclusions:

  • Identified a novel TRIM21-ASK1 signaling axis that drives pathological cardiac hypertrophy.
  • TRIM21 promotes cardiac hypertrophy through ASK1-mediated activation of JNK/p38 MAPK pathways.
  • TRIM21 represents a potential therapeutic target for treating hypertrophic heart disease and heart failure.

Keywords:
ASK1MAPKTRIM21pathological cardiac hypertrophypolyubiquitination

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