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

ABSTRACT 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 Zer1 fl/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.