Deubiquitinase USP29 Ameliorates Pathological Cardiac Hypertrophy Through Inhibiting TAK1

The identification of key factors involved in pathological cardiac hypertrophy is crucial to exploring novel treatments for heart failure. In this study, we elucidated the role of Ubiquitin-specific protease 29 (USP29), a deubiquitinase, in pressure overload-induced cardiac hypertrophy. Genetic knockout of USP29 in mice significantly exacerbated TAC-induced heart hypertrophy, dysfunction, and fibrosis; whereas overexpression of USP29 in cardiomyocytes attenuated the hypertrophic response. Similarly, USP29 markedly alleviated PE-induced hypertrophy of primary neonatal rat cardiomyocytes. Mechanistically, the cardio-protective effects mediated by USP29 were attributed to its suppression of transforming growth factor β-activated kinase 1 (TAK1)-JNK/P38 signaling pathway activation. Collectively, our study suggests that targeting either USP29 or its interaction with TAK1 could represent an innovative therapeutic strategy for treating heart failure and cardiac hypertrophy. To investigate the impact of USP29 on pathological cardiac hypertrophy, we generated a global mouse strain with Usp29 knockout (USP29-KO, C57BL/6 background mice).Subsequently, both USP29-KO and control mice (littermate WT mice) were subjected to transverse aortic constriction ( TAC ) for 4 weeks.We then performed gene expression analysis using data obtained from RNA-seq of 6 different left ventricular myocardial tissues. Comparative gene expression analysis of RNA-seq data for left ventricular myocardial tissues from USP29-KO mice or littermate WT mice treated with TAC for 4 weeks.