Acetate enhances neuronal plasticity and reduces ischemic brain injury by promoting tau protein lactylation.

Ischemic stroke remains a major contributor to neurological disability worldwide, with limited options for promoting brain recovery. While acetate is known to exert various pathophysiological effects on the brain, its potential to mitigate brain injury following ischemic stroke and the underlying mechanisms remain poorly understood. In particular, how acetate engage astrocyte-neuron metabolic coupling and influence tau protein modifications remains to be clarified. Here, we found that brain acetate levels were elevated by 1.51-fold after ischemia and reperfusion for 24 h. The accumulated acetate in the brain improved survival with a 7-day survival rate of 61% in the acetate group versus 47% in the control group and attenuated brain injury. Mechanistically, acetate stimulated the astrocyte-neuron lactate shuttle (ANLS), leading to increased tau protein lactylation in neurons. This process was blocked by Su3118, a pharmacological inhibitor of monocarboxylate transporter 1/4 (MCT1/4), confirming their involvement. We further revealed that site-specific tau lactylation enhanced neuronal plasticity and rendered the brain less sensitive to ischemic stroke. Taken together, our findings unveil that acetate enhances astrocytic glucose uptake and glycolysis, stimulates ANLS, and promotes tau protein lactylation in neurons, thereby contributing to its neuroprotective role, highlighting its relevance for developing acetate-based interventions in stroke recovery.