Non‐Histone Lactylation: A New Frontier in Cerebral Ischemia‐Reperfusion Injury

ABSTRACT Reperfusion therapy is the mainstay of treatment for ischemic stroke (IS) but frequently exacerbates secondary injury. Following cerebral ischemia and hypoxia, lactate accumulates markedly. Traditionally regarded as a metabolic byproduct, lactate has gained new significance with the discovery of protein lactylation. In addition to experimental evidence, recent computational models have been developed to predict potential proteins and sites of lactylation. Nevertheless, the roles of lactate and lactylation in cerebral ischemia reperfusion (I/R) injury remain unclear and even controversial. Current studies suggest that ischemic and reperfusion phases differ in their pathological changes, and accumulating evidence indicates that non‐histone lactylation may aggravate injury. Proposed mechanisms include the promotion of neuronal death, exacerbation of neuroinflammation, modulation of mitochondrial function, and alteration of angiogenesis. Furthermore, potential crosstalk between lactylation and other post‐translational modifications, whether synergistic or antagonistic, may influence disease progression, yet such interactions in cerebral I/R injury have not been systematically investigated. Current strategies to modulate lactylation include targeting lactate levels, lactate dehydrogenase, transporters, and modifying enzymes. This review summarizes multiple factors influencing non‐histone lactylation and discusses potential intervention strategies, highlighting their advantages and limitations and providing new perspectives for the treatment of cerebral I/R injury.