synthesize a cell‐penetrating peptide Tat‐SIRT5‐CTM and reveal that this peptide specifically blocked the interaction of SIRT5 with ANXA1, led to SIRT5 degradation and thereby inhibiting SIRT5‐mediated desuccinylation of ANXA1, which, in turn, alleviated microglia‐induced neuroinflammation, and eventually protected neurons against ischemic stroke. This evidence concerns the gene ANXA1 and ischemic stroke.