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Purpose <p>Pathological cardiac hypertrophy is a major driver of heart failure with limited therapeutic options. This study aimed to identify novel molecular regulators and therapeutic targets for pathological cardiac remodeling.</p> Methods <p>UBR5 expression was quantified via qRT-PCR and Western blot in TAC-induced hypertrophic mouse hearts and Ang II-treated neonatal rat cardiomyocytes (NRCMs). Cardiac-specific Ubr5 knockout mice and NRCMs with UBR5 overexpression were generated to assess hypertrophic phenotypes (cardiac weight/tibia length ratio, echocardiography, fetal gene expression). Mechanistic investigations employed co-immunoprecipitation to confirm UBR5-Nrf2 binding, followed by in vitro ubiquitination assays to demonstrate K48-linked polyubiquitination of Nrf2. </p> Results <p>UBR5 was significantly upregulated in hypertrophic hearts (TAC mice) and Ang II-stimulated NRCMs. Cardiac-specific Ubr5 KO markedly attenuated TAC-induced hypertrophy, cardiac dysfunction, and fetal gene reactivation. Conversely, UBR5 overexpression exacerbated Ang II-induced hypertrophy. Mechanistically, UBR5 directly bound Nrf2, promoting its K48-linked polyubiquitination and proteasomal degradation, thereby suppressing heme oxygenase-1 (HO-1) expression. Rescue experiments confirmed that HO-1 downregulation abolished the protective effect of Ubr5 KO, while Nrf2 ablation eliminated UBR5-mediated pro-hypertrophic effects.</p> Conclusion <p>UBR5 drives pathological cardiac hypertrophy by ubiquitin-mediated destabilization of Nrf2 and subsequent inhibition of the Nrf2/HO-1 cytoprotective axis. Targeting UBR5 represents a promising therapeutic strategy for treating pathological cardiac hypertrophy and heart failure.</p>

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E3 Ubiquitin Ligase UBR5 Aggravates Cardiac Hypertrophy Via Inhibiting Nrf2/HO-1 Pathway

  • 期刊论文

  • 发表日期：

    2026年3月13日

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  • Guofeng Zhu,
  • Haiyang Fang,
  • Congcong Xu,
  • Kai Zhu,
  • Tieqiu Huang,
  • Wei Zhou,
  • Min Huang

摘要

Purpose

Pathological cardiac hypertrophy is a major driver of heart failure with limited therapeutic options. This study aimed to identify novel molecular regulators and therapeutic targets for pathological cardiac remodeling.

Methods

UBR5 expression was quantified via qRT-PCR and Western blot in TAC-induced hypertrophic mouse hearts and Ang II-treated neonatal rat cardiomyocytes (NRCMs). Cardiac-specific Ubr5 knockout mice and NRCMs with UBR5 overexpression were generated to assess hypertrophic phenotypes (cardiac weight/tibia length ratio, echocardiography, fetal gene expression). Mechanistic investigations employed co-immunoprecipitation to confirm UBR5-Nrf2 binding, followed by in vitro ubiquitination assays to demonstrate K48-linked polyubiquitination of Nrf2.

Results

UBR5 was significantly upregulated in hypertrophic hearts (TAC mice) and Ang II-stimulated NRCMs. Cardiac-specific Ubr5 KO markedly attenuated TAC-induced hypertrophy, cardiac dysfunction, and fetal gene reactivation. Conversely, UBR5 overexpression exacerbated Ang II-induced hypertrophy. Mechanistically, UBR5 directly bound Nrf2, promoting its K48-linked polyubiquitination and proteasomal degradation, thereby suppressing heme oxygenase-1 (HO-1) expression. Rescue experiments confirmed that HO-1 downregulation abolished the protective effect of Ubr5 KO, while Nrf2 ablation eliminated UBR5-mediated pro-hypertrophic effects.

Conclusion

UBR5 drives pathological cardiac hypertrophy by ubiquitin-mediated destabilization of Nrf2 and subsequent inhibition of the Nrf2/HO-1 cytoprotective axis. Targeting UBR5 represents a promising therapeutic strategy for treating pathological cardiac hypertrophy and heart failure.