Finally, we quantified the infarct volume, neurological damage, cognitive function, motor coordination, synaptic plasticity, and levels of autophagy, inflammation, and apoptosis in MCAO/R model mice treated with Tat-NTS peptide, which provided conclusive evidence that Tat-NTS peptide regulated ANXA1 SUMOylation in microglia/macrophages and exerted a robust neuroprotective effect against cerebral ischemia/reperfusion injury. Here, ANXA1 is linked to brain ischemia.