ZER1 Restrains Pressure Overload-Induced Cardiac Remodeling by Targeting DVL2 for Gly/N-Degron-Dependent Degradation.

Pathological cardiac hypertrophy drives heart failure progression, but the proteostatic mechanisms restraining maladaptive remodeling remain poorly defined. Here, we identify Zyg-11-related regulator 1 (ZER1) as a previously unrecognized Gly/N-degron proteostatic regulator of pressure overload-induced remodeling. Failing human hearts and mouse transverse aortic constriction (TAC) hearts show suppression of a CRL2/Gly-N-degron signature and reduced ZER1 abundance. Global and cardiomyocyte-specific Zer1 loss exacerbates TAC-induced hypertrophy, fibrosis, and systolic dysfunction. Mechanistically, ZER1 directly binds disheveled segment polarity protein 2 (DVL2) in an N-terminus-dependent manner and promotes its K48-linked polyubiquitination and proteasomal degradation, thereby limiting DVL2 accumulation and downstream CaMKII-HDAC4-MEF2C signaling. Cardiomyocyte-targeted Dvl2 knockdown abolishes the phenotypic differences between Zer1fl/fl and Zer1-cKO mice after TAC. WWP1 knockdown cannot rescue the phenotype induced by ZER1 deletion, demonstrating that ZER1 is required for Wwp1 knockdown-mediated protection against pressure overload-induced cardiac remodeling. Importantly, cardiomyocyte-selective AAV9-mediated restoration of ZER1 after TAC onset attenuates established remodeling and preserves cardiac function. Together, these findings define a ZER1-DVL2 proteostatic checkpoint that links Gly/N-degron-dependent protein quality control to pathological cardiac remodeling and highlights ZER1 as a potential therapeutic target for heart failure.