Acute kidney injury (AKI) refers to a clinical syndrome that occurs as a result of a rapid decline in renal function caused by multiple factors.Renal ischemia/reperfusion (I/R) injury is one of the main causes of AKI and has a high incidence and mortality.However,the specific pathogenesis of renal I/R injury is still unclear.In recent years,a major breakthrough has been made in the study of endoplasmic reticulum stress (ERS)-mediated apoptosis in I/R injury.It has been reported that miRNAs play protective roles in ischemic/reperfused organs,but the molecular mechanisms have not been investigated deeply.In this study,the renal I/R mouse model was used to explore the roles of miR-124 in ERS and in renal I/R injury.The weste blot results showed that the expression levels of ERS-related proteins IRE-1α,XBP-1,and glucose-regulated protein 78 (GRP78) were significantly increased in the I/R model group when compared with those in the control group.Meanwhile,qPCR results showed that miR-124 expression was decreased in the I/R injury model,and overexpression of miR-124 using miR-124 mimics effectively reduced the expression of ERS-related proteins and alleviated renal I/R injury.In addition,luciferase reporter assay was performed,and the results showed that IRE-1α and miR-124 may have direct interaction.In conclusion,our data indicated that miR-124 was a negative regulator of ERS via binding to IRE-1α,ultimately conferring its protective effect on the kidney,which demonstrates the regulatory mechanism of miR-124 in renal I/R injury and provides new ideas and methods for the prevention and treatment of renal I/R injury.