摘要We previously found that monocyte locomotion inhibitory factor has a neuroprotective effect on ischemic brain injury during the acute phase of stroke. Therefore, we modified the structure of an anti-inflammatory monocyte locomotion inhibitory factor peptide to construct an active cyclic peptide—Cyclo (MQCNS) (LZ-3)—and investigated its effects on ischemic stroke. In this study, we established a rat model of ischemic stroke by occluding the middle cerebral artery and then administered LZ-3 (2 or 4 mg/kg) via the tail vein for 7 consecutive days. Our results showed that LZ-3 (2 or 4 mg/kg) substantially decreased infarct volume, reduced cortical nerve cell death, improved neurological function, reduced cortical and hippocampal injury, and decreased the levels of inflammatory factors in the blood and brain tissues. In a well-differentiated, oxygen-glucose deprivation/reoxygenation-induced BV2 cell model of post-stroke, LZ-3 (100 μM) inhibited the JAK1-STAT6 signaling pathway. LZ-3 regulated microglia/macrophage polarization from the M1 to the M2 type and inhibited microglia/macrophage phagocytosis and migration via the JAK1/STAT6 signaling pathway. To conclude, LZ-3 regulates microglial activation by inhibiting the JAK1/STAT6 signaling pathway and improves functional recovery post-stroke.