The endoplasmic reticulum (ER) stress plays an important role in myocardial ischemia/reperfusion (MYR) injury. SERPI, the stress-associated endoplasmic reticulum protein 1, is involved in regulating ER stress response. However, whether it associates with MI/R injury is not identified. Here, we show that SERPI is induced in the mouse heart after MI/R injury as well as in H9c2 cells under hypoxia/reoxygenation (H/R) treatment. Additionally, SERPI overexpression reduces H/R-induced H9c2 apoptosis. Moreover, SERP1 overexpression suppresses H/R-induced ER stress and activates JAK2/STAT3 pathway. Furthermore, JAK2/ STAT3 pathway inhibition by the specific inhibitor JSI-124 minimizes the suppressive effect of SERPI overexpression on H/R-induced ER stress and H9c2 apoptosis. Together, these results uncover the protection of SERPI against H/R-induced H9c2 apoptosis and further relate it to JAK2/STAT3 pathway-dependent attenuation of ER stress. This study suggests SERPI as a potential regulator invovled in the pathophysiology of MI/R injury. (C) 2018 Published by Elsevier Inc.