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Peer-reviewedCC BY 4.0Experimental & Molecular Medicine

Cardiomyocyte-enriched OTUD5 alleviates pathological myocardial hypertrophy by deubiquitinating STAT3 and modulating the STAT3–PGC-1α axis

  • Bozhi Ye1,2,3
  • Yucheng Jiang2,3
  • Zhaozheng Zheng2,3
  • Yanhong Jin2
  • Yingjie Liao2
  • Zhihan Jia2
  • Wante Lin2
  • Diyun Xu2
  • Jibo Han2
  • Zimin Fang2
  • Naijin Zhang4
  • Peiren Shan2
2 more authors
  • Gaojun Wu2
  • Guang Liang1,2,3,5
5 affiliations
  1. 1Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  2. 2Department of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  3. 3Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
  4. 4Department of Cardiology, The First Hospital of China Medical University, Shenyang, People’s Republic of China
  5. 5School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
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Abstract

Pathological cardiac hypertrophy presents a important public health challenge, particularly in aging populations, highlighting the urgent need for novel therapeutic targets. This study investigates the role and molecular mechanisms of OTUD5 in pathological cardiac hypertrophy. OTUD5 expression is greatly increased in cardiomyocytes from hypertrophic hearts. Deleting cardiomyocyte-specific OTUD5 exacerbates myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC). By contrast, targeted overexpression of OTUD5 in cardiomyocytes alleviates Ang II-induced pathological hypertrophy. Mechanistically, we demonstrate that OTUD5 regulates STAT3 activity by removing the K63-linked ubiquitin chain at lysine 283 (K283) on STAT3 through its C224 residue. This process inhibits both phosphorylation and nuclear translocation of STAT3, effectively relieving its transcriptional repression of PGC1α and enhancing mitochondrial function within cardiomyocytes. Our research uncovers a new OTUD5–STAT3–PGC1α axis that modulates mitochondrial bioenergetics, suggesting it as a potential therapeutic target for pathological cardiac hypertrophy.

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Cite

BibTeXRIS
BibTeX
@article{ye2026cardiomyocyteenriched,
  title = {{Cardiomyocyte-enriched OTUD5 alleviates pathological myocardial hypertrophy by deubiquitinating STAT3 and modulating the STAT3–PGC-1α axis}},
  author = {Bozhi Ye and Yucheng Jiang and Zhaozheng Zheng and Yanhong Jin and Yingjie Liao and Zhihan Jia and Wante Lin and Diyun Xu and Jibo Han and Zimin Fang and Naijin Zhang and Peiren Shan and Gaojun Wu and Guang Liang},
  journal = {Experimental \& Molecular Medicine},
  year = {2026},
  month = oct,
  doi = {10.1038/s12276-026-01870-5},
  url = {https://doi.org/10.1038/s12276-026-01870-5},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cardiomyocyte-enriched OTUD5 alleviates pathological myocardial hypertrophy by deubiquitinating STAT3 and modulating the STAT3–PGC-1α axis
AU  - Bozhi Ye
AU  - Yucheng Jiang
AU  - Zhaozheng Zheng
AU  - Yanhong Jin
AU  - Yingjie Liao
AU  - Zhihan Jia
AU  - Wante Lin
AU  - Diyun Xu
AU  - Jibo Han
AU  - Zimin Fang
AU  - Naijin Zhang
AU  - Peiren Shan
AU  - Gaojun Wu
AU  - Guang Liang
PY  - 2026
DA  - 2026/10/16
JO  - Experimental & Molecular Medicine
DO  - 10.1038/s12276-026-01870-5
UR  - https://doi.org/10.1038/s12276-026-01870-5
AB  - Pathological cardiac hypertrophy presents a important public health challenge, particularly in aging populations, highlighting the urgent need for novel therapeutic targets. This study investigates the role and molecular mechanisms of OTUD5 in pathological cardiac hypertrophy. OTUD5 expression is greatly increased in cardiomyocytes from hypertrophic hearts. Deleting cardiomyocyte-specific OTUD5 exacerbates myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC). By contrast, targeted overexpression of OTUD5 in cardiomyocytes alleviates Ang II-induced pathological hypertrophy. Mechanistically, we demonstrate that OTUD5 regulates STAT3 activity by removing the K63-linked ubiquitin chain at lysine 283 (K283) on STAT3 through its C224 residue. This process inhibits both phosphorylation and nuclear translocation of STAT3, effectively relieving its transcriptional repression of PGC1α and enhancing mitochondrial function within cardiomyocytes. Our research uncovers a new OTUD5–STAT3–PGC1α axis that modulates mitochondrial bioenergetics, suggesting it as a potential therapeutic target for pathological cardiac hypertrophy.
SN  - 1226-3613
SN  - 2092-6413
ER  -