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Cardiomyocyte-derived YOD1 promotes pathological cardiac hypertrophy by deubiquitinating and stabilizing STAT3

Bozhi Ye1,2,3, Wante Lin1, Yucheng Jiang3

  • 1Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Science Advances
|June 25, 2025
PubMed

Insights

Researchers discovered that the deubiquitinating enzyme YOD1 stabilizes STAT3, reducing pathological cardiac hypertrophy. Inhibiting YOD1 or STAT3 mitigated cardiac remodeling, offering new therapeutic targets for heart conditions.

Area of Science:

  • Cardiovascular Biology
  • Molecular Mechanisms of Disease
  • Biochemistry

Background:

  • Pathological cardiac hypertrophy remains a significant clinical challenge.
  • Identifying novel molecular targets is crucial for developing effective therapies.
  • The role of deubiquitinating enzymes in cardiac remodeling is not fully understood.

Purpose of the Study:

  • To investigate the role of the deubiquitinating enzyme YOD1 in pathological cardiac hypertrophy.
  • To identify novel interacting partners and downstream pathways of YOD1 in cardiomyocytes.
  • To explore the therapeutic potential of targeting the YOD1-STAT3 axis.

Main Methods:

  • Analysis of YOD1 expression in human and mouse hypertrophic hearts.
  • Generation of cardiomyocyte-specific Yod1 knockout mouse models.
  • Proteomic analysis to identify YOD1 substrates.
  • Biochemical assays to confirm YOD1-STAT3 interaction and deubiquitination.
  • In vivo studies using angiotensin II infusion and transverse aortic constriction (TAC) models.
  • Pharmacological inhibition of YOD1 and STAT3.

Main Results:

  • YOD1 expression was moderately elevated in hypertrophic myocardium.
  • Cardiomyocyte-specific YOD1 knockout attenuated Ang II- and TAC-induced cardiac hypertrophy.
  • Proteomic analysis identified STAT3 as a substrate of YOD1.
  • YOD1 deubiquitinates K97 on STAT3, stabilizing it and promoting nuclear translocation.
  • STAT3 inhibition reversed the antihypertrophic effects of YOD1 deficiency.
  • Pharmacological YOD1 inhibition reduced Ang II-induced ventricular remodeling.

Conclusions:

  • YOD1 plays a critical role in regulating pathological cardiac hypertrophy.
  • A novel YOD1-STAT3 signaling axis is identified in cardiac hypertrophy.
  • Targeting the YOD1-STAT3 pathway offers a promising therapeutic strategy for cardiac hypertrophy.

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