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Background <p>Pathological cardiac hypertrophy frequently leads to heart failure (HF). UBA1, the key E1 ubiquitin-activating enzyme, initiates ubiquitin-proteasome signaling and contributes to various diseases, yet its mechanism in cardiac hypertrophy remains unclear.</p> Methods <p>Cardiac hypertrophy model was induced by either Ang II stimulation or TAC in vitro and in vivo. Mice received rAAV9-UBA1-siRNA or rAAV9-UBA1 for UBA1 knockdown or overexpression, respectively.</p> Results <p>We found UBA1 upregulated in murine and human hypertrophic hearts. Cardiomyocyte-specific UBA1 knockdown protected against TAC-induced hypertrophy, fibrosis, oxidative stress, and dysfunction, with downregulation of ATG5 and autophagy induction, whereas myocardial UBA1 overexpression exacerbated these effects. Mechanistically, UBA1 directly interacted with ATG5 and promoted its ubiquitination for degradation, leading to autophagy inactivation and hypertrophy. Furthermore, ATG5 deletion abrogated the protection of UBA1 knockdown against cardiomyocyte hypertrophy.</p> Conclusions <p>UBA1 regulates cardiac hypertrophy through suppression of ATG5-mediated autophagy and propose UBA1 as a therapeutic target for hypertrophic cardiomyopathy.</p>

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UBA1 promotes cardiac hypertrophy by suppressing autophagy via targeting ATG5 for ubiquitination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Qiu-Yue Lin,
  • Wei-Jia Yu,
  • Jia-Xin Li,
  • Wen-Xi Jiang,
  • Shu-Jing Liu,
  • Hai-Lian Bi,
  • Hui-Hua Li

摘要

Background

Pathological cardiac hypertrophy frequently leads to heart failure (HF). UBA1, the key E1 ubiquitin-activating enzyme, initiates ubiquitin-proteasome signaling and contributes to various diseases, yet its mechanism in cardiac hypertrophy remains unclear.

Methods

Cardiac hypertrophy model was induced by either Ang II stimulation or TAC in vitro and in vivo. Mice received rAAV9-UBA1-siRNA or rAAV9-UBA1 for UBA1 knockdown or overexpression, respectively.

Results

We found UBA1 upregulated in murine and human hypertrophic hearts. Cardiomyocyte-specific UBA1 knockdown protected against TAC-induced hypertrophy, fibrosis, oxidative stress, and dysfunction, with downregulation of ATG5 and autophagy induction, whereas myocardial UBA1 overexpression exacerbated these effects. Mechanistically, UBA1 directly interacted with ATG5 and promoted its ubiquitination for degradation, leading to autophagy inactivation and hypertrophy. Furthermore, ATG5 deletion abrogated the protection of UBA1 knockdown against cardiomyocyte hypertrophy.

Conclusions

UBA1 regulates cardiac hypertrophy through suppression of ATG5-mediated autophagy and propose UBA1 as a therapeutic target for hypertrophic cardiomyopathy.