Cardiomyocyte OTUD7b drives diabetic cardiomyopathy via deubiquitinating and stabilizing TAK1.

Authors

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

Published in

Acta pharmacologica Sinica. Aug 03, 2026. Epub Aug 03, 2026.

Abstract

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.

PMID:
42547542
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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