In this study, using primary cardiomyocytes, cardiac-specific knockout of SOCS3 (SOCS3cko) or overexpression mice infected with rAAV9-SOCS3, we found that SOCS3-GRP78-ER stress signaling was essential for the transition from cardiac hypertrophy to HF during pressure overload, we found that SOCS3 acts as a negative regulator of cardiac hypertrophy and dysfunction induced by pressure overload by targeting GRP78 for ubiquitination and degradation by the proteasome. This evidence concerns the gene HSPA5 and hydrops fetalis.