A cell‐penetrating peptide exerts therapeutic effects against ischemic stroke by mediating the lysosomal degradation of sirtuin 5

Abstract Stroke is a major public health concern worldwide. The lack of effective therapies heightens the need for new therapeutic agents. Previous study identified sirtuin 5 (SIRT5) as a positive regulator of microglia‐induced excessive neuroinflammation following ischemic stroke. Interventions targeting SIRT5 should therefore alleviate neuroinflammation and protect against ischemic stroke. Here, we synthesized a membrane‐permeable peptide specifically bound to SIRT5 through a chaperone‐mediated autophagy targeting motif (Tat‐SIRT5‐CTM) and examined its therapeutic effect in vitro and in vivo. First, in primary microglia, Tat‐SIRT5‐CTM suppressed the binding of SIRT5 with annexin‐A1 (ANXA1), leading to SIRT5 degradation and thus inhibition of SIRT5‐mediated desuccinylation of ANXA1, followed by increased membrane accumulation and secretion of ANXA1. These changes, in turn, alleviated microglia‐induced neuroinflammation. Moreover, following intravenous injection, Tat‐SIRT5‐CTM could efficiently pass through the blood‒brain barrier. Importantly, systemic administration of Tat‐SIRT5‐CTM reduced the brain infarct area and neuronal loss, mitigated neurological deficit scores, and improved long‐term neurological functions in a mouse model of ischemic stroke. Furthermore, no toxicity was observed when high doses Tat‐SIRT5‐CTM were injected into nonischemic mice. Collectively, our study reveals the promising efficacy of the peptide‐directed lysosomal degradation of SIRT5 and suggests it as an effective therapeutic approach for the treatment of ischemic stroke.