<b>Raw data associated with astrocyte-derived lactate aggravates the brain injury of ischemic stroke by promoting the formation of protein lactylation</b>

The roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke remains unclear. Here, we found that accumulated lactate at the ischemia stage aggravates brain injury by inducing neuronal death and A1 astrocytes. The detrimental role was ascribed to the increased lactate-derived protein lysine lactylation (Kla) that mainly located in neurons because pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains, and conditionally inhibited lactate production in astrocytes also showed obviously decreased protein Kla level and cerebral infarction volume. Furthermore, blocking the protein Kla formation significantly alleviates the brain injury of cerebral ischemia with a reduction in the protein Kla level. Our findings highlight a novel role and mechanism for the accumulated brain lactate content that has potential as a therapeutic target for the treatment of ischemic stroke.