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<p>Deubiquitinating enzymes (DUBs) are critically involved in diabetic cardiomyopathy (DCM), yet the function of OTU domain-containing protein 7B (OTUD7b), a recently identified DUB, in DCM remains unknown. Here, we identified that OTUD7b expression was significantly elevated in cardiomyocytes from both type 1 and type 2 diabetic mouse hearts. Cardiomyocyte-specific deletion of OTUD7b ameliorated cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice, without affecting systemic hyperglycemia. Mechanistically, combining ubiquitinome and interactome analyses, we identified transforming growth factor β-activated kinase 1 (TAK1) as a direct substrate of OTUD7b in cardiomyocytes. Under diabetic conditions, OTUD7b binds to TAK1 via its zinc finger domain and catalyzes K48-linked deubiquitination at the K346 of TAK1, thereby enhancing TAK1 protein stability. This OTUD7b-mediated stabilization increased the levels of both TAK1 and p-TAK1, which led to hyperactivation of the TAK1-MAPK (JNK/p38) axis, subsequently promoting extrinsic apoptosis and inflammatory responses in cardiomyocytes. Crucially, cardiomyocyte-specific reconstitution of a deubiquitination-resistant TAK1-K346R mutant in diabetic mice completely abolished the cardioprotective effects of OTUD7b deficiency, confirming that OTUD7b drives DCM primarily through deubiquitinating TAK1 at K346. Taken together, our study unveils a novel OTUD7b-TAK1 axis in cardiomyocytes driving diabetic heart injury and positions OTUD7b as a promising therapeutic target for DCM.</p><p></p>

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Cardiomyocyte OTUD7b drives diabetic cardiomyopathy via deubiquitinating and stabilizing TAK1

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Xue Han,
  • Guo-xuan Liu,
  • Jia-ning Zheng,
  • Ming-yang He,
  • Li Zhuang,
  • Jia-jia Zhang,
  • Jie Tong,
  • Zhu-qi Huang,
  • Yu-rou Wu,
  • Tong-qing Zhou,
  • Ju-lin Min,
  • Ze-ping Zhang,
  • Ning Zhu,
  • Qiao-juan Shi,
  • Wen-bing Jiang,
  • Hua-zhong Ying,
  • Guang Liang

摘要

Deubiquitinating enzymes (DUBs) are critically involved in diabetic cardiomyopathy (DCM), yet the function of OTU domain-containing protein 7B (OTUD7b), a recently identified DUB, in DCM remains unknown. Here, we identified that OTUD7b expression was significantly elevated in cardiomyocytes from both type 1 and type 2 diabetic mouse hearts. Cardiomyocyte-specific deletion of OTUD7b ameliorated cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice, without affecting systemic hyperglycemia. Mechanistically, combining ubiquitinome and interactome analyses, we identified transforming growth factor β-activated kinase 1 (TAK1) as a direct substrate of OTUD7b in cardiomyocytes. Under diabetic conditions, OTUD7b binds to TAK1 via its zinc finger domain and catalyzes K48-linked deubiquitination at the K346 of TAK1, thereby enhancing TAK1 protein stability. This OTUD7b-mediated stabilization increased the levels of both TAK1 and p-TAK1, which led to hyperactivation of the TAK1-MAPK (JNK/p38) axis, subsequently promoting extrinsic apoptosis and inflammatory responses in cardiomyocytes. Crucially, cardiomyocyte-specific reconstitution of a deubiquitination-resistant TAK1-K346R mutant in diabetic mice completely abolished the cardioprotective effects of OTUD7b deficiency, confirming that OTUD7b drives DCM primarily through deubiquitinating TAK1 at K346. Taken together, our study unveils a novel OTUD7b-TAK1 axis in cardiomyocytes driving diabetic heart injury and positions OTUD7b as a promising therapeutic target for DCM.