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Neuregulin-1 (NRG-1) is a stress-mediated growth factor secreted by cardiovascular endothelial cells and provides the protection to myocardial cells, but the underlying mechanisms are not fully understood.This study aimed to demonstrate that NRG-1 protects myocardial cells exposed to oxidative injury by regulating endoplasmic reticulum stress.Neonatal rat cardiac myocytes (NRCMs) were isolated and treated with H2O2 as a cellular model of endoplasmic reticulum stress.NRCMs were pretreated with different concentrations of NRG-1.We found that NRG-1 increased the viability and reduced the apoptosis of NRCMs treated by H2O2.Moreover, NRG-1 reduced LDH level, increased SOD activity, and decreased MDA content in NRCMs treated by H2O2.Finally, we demonstrated that NRG-1 alleviated ER stress and decreased CHOP and GRP78 protein levels in NRCMs treated by H2O2.Taken together, these data indicate that NRG-1 relieves oxidative and ER stress in NRCMs and suggest that NRG-1 is a promising agent for cardioprotection.