Importantly, GRP78 knockdown or inhibition of ER stress with 4-PBA not only effectively improved TAC-induced cardiac contractile dysfunction, hypertrophy, and fibrosis, but also suppressed ER stress and mitophagy in SOCS3f/f and SOCS3cko hearts (Figures 6, 7), suggesting that GRP78-mediated ER stress plays an important role in the development of cardiac hypertrophy-related dysfunction. This evidence concerns the gene HSPA5 and cardiac hypertrophy.