Deubiquitinase OTUB1 attenuates pathological cardiac hypertrophy by activating the AMPK signaling pathway

Cardiac hypertrophy, a response to pathological stimuli, eventually progresses to heart failure. Ovarian tumor-associated proteinase B1 (OTUB1), a deubiquitinase of the ovarian tumor (OUT) family, regulates inflammation, cell survival, and oxidative stress in various diseases, but its role in cardiac hypertrophy remains unclear. Here, we investigated OTUB1 expression, function, and mechanism in pathological cardiac hypertrophy. OTUB1 expression was significantly downregulated in human hypertrophic hearts, transverse aortic constriction (TAC)-induced mouse hypertrophic hearts, and phenylephrine-stimulated neonatal rat ventricular myocytes (NRVMs). OTUB1 knockout (KO) mice exhibited exacerbated TAC-induced cardiac hypertrophy, dysfunction, and fetal gene reactivation, whereas OTUB1 overexpression attenuated PE-induced cardiomyocyte enlargement. Mechanistically, OTUB1 directly bound to, deubiquitinated, and stabilized Sirt2, thereby promoting AMPK phosphorylation. Silencing Sirt2 abolished the anti-hypertrophic effects of OTUB1 and blocked AMPK activation. In conclusion, OTUB1 protects against pathological cardiac hypertrophy by stabilizing Sirt2 and activating the AMPK signaling pathway, suggesting that OTUB1 is a promising therapeutic target for hypertrophy-associated heart failure.