Non-histone lactylation: A new frontier in cerebral ischemia-reperfusion injury

In this paper, we comprehensively review the role of non-histone protein lactylation in cerebral ischemia–reperfusion (I/R) injury from multiple perspectives, including its dynamic alterations during ischemic and reperfusion phases, regulatory mechanisms involved in key pathological processes such as neuroinflammation, neuronal death, mitochondrial dysfunction, and angiogenesis, as well as its crosstalk with other post-translational modifications (PTMs), strategies for site identification, and potential therapeutic interventions. This review summarizes the determinants influencing non-histone lactylation, critically evaluates the advantages and limitations of current intervention strategies, and proposes novel insights for the prevention and rehabilitation of cerebral I/R injury. Importantly, since research on non-histone lactylation in cerebral I/R injury remains at a preliminary stage—with the roles of lactate and lactylation still ambiguous or even controversial, and a lack of systematic exploration of their interplay with other PTMs—this review aims to bridge these knowledge gaps and advance the mechanistic understanding of cerebral I/R injury at the epigenetic and metabolic levels.