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OBJECTIVE The aim of this study was to clarify the role of microRNA-433-5p (miRNA-433-5p) in influencing pathological lesions following acute spinal cord injury (SCI) by targeting mitogen-activated protein kinase 1 (MAPK1). PATIENTS AND METHODS SCI model was successfully established in mice by performing hitting injury procedures. Serum levels of miRNA-433-5p and MAPK1 in SCI patients and mice were determined. Grip strengths of both forelimbs in SCI mice and controls were determined. Dual-Luciferase reporter gene assay was applied to verify the binding relation between miRNA-433-5p and MAPK1. After overexpression of miRNA-433-5p and MAPK1 in vivo, the grip strength changes in SCI mice were assessed. Furthermore, the protein level of inflammatory factor iNOS in 293T cells influenced by miRNA-433-5p and MAPK1 was detected by Western blot. RESULTS MiRNA-433-5p was significantly downregulated in the serum of SCI patients and mice, whereas MAPK1 was up-regulated. Grip strengths of SCI mice were significantly lower than those of controls at different postoperative time points. However, this could be markedly reversed by the in vivo overexpression of miRNA-433-5p. Western blot indicated that the protein level of iNOS was remarkably downregulated in 293T cells overexpressing miRNA-433-5p. MAPK1 was confirmed as the target of miRNA-433-5p, whose expression level was negatively regulated by miRNA-433-5p. Importantly, MAPK1 partially reversed the protective role of miRNA-433-5p in grip strength of SCI mice and inflammatory response at post-SCI. CONCLUSIONS Overexpression of miRNA-433-5p protects SCI-induced motor dysfunction and inflammatory response by targeting MAPK1.