--- - |2- The key findings of this study support the notion that miR‐150 under‐expression‐mediated direct promotion of Mal protects CNN functions through the activation of ERK1/2 axis, and underscore the concept that miR‐150 may represent a novel pharmacological target for ischemic stroke intervention. Ischemic stroke, caused by the blockage of blood supply, is a major cause of death worldwide. For identifying potential candidates, we explored the effects microRNA‐150 (miR‐150) has on ischemic stroke and its underlying mechanism by developing a stable middle cerebral artery occlusion (MCAO) rat model. Gene expression microarray analysis was performed to screen differentially expressed genes associated with MCAO. We evaluated the expression of miR‐150 and Mal and the status of ERK1/2 axis in the brain tissues of MCAO rats. Then the cerebral cortical neurons (CCNs) were obtained and introduced with elevated or suppressed miR‐150 or silenced Mal to validate regulatory mechanisms for miR‐150 governing Mal in vitro. The relationship between miR‐150 and Mal was verified by dual luciferase reporter gene assay. Besides, cell growth and apoptosis of CCNs were detected by means of MTT assay and flow cytometry analyses. We identified Mal as a downregulated gene in MCAO, based on the microarray data of GSE16561. MiR‐150 was over‐expressed and negatively targeted Mal in the brain tissues obtained from MCAO rats and their CCNs. Increasing miR‐150 blocked the ERK1/2 axis, resulting in an inhibited cell growth of CNNs but an enhanced apoptosis. Furthermore, MiR‐150 inhibition was observed to have effects on CNNs as opposed to those inhibited by miR‐150 promotion. The key findings of this study support the notion that miR‐150 under‐expression‐mediated direct promotion of Mal protects CNN functions through the activation of the ERK1/2 axis, and underscore the concept that miR‐150 may represent a novel pharmacological target for ischemic stroke intervention. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1477-1490, February 2019. '