Novel acylation modifications in cerebrovascular disease: Molecular mechanisms, crosstalk and therapeutic potential

Secondary injury in cerebrovascular disease involves energy failure, oxidative stress, neuroinflammation, blood-brain barrier disruption and neurovascular unit dysfunction. Novel lysine acylations, including lactylation, succinylation, beta-hydroxybutyrylation and crotonylation, have emerged as interfaces through which metabolic changes in lactate, succinate, ketone bodies and short-chain acyl-CoA species are translated into transcriptional regulation and altered protein function. This review organizes the evidence according to a framework that links metabolic donors, writer and eraser enzymes, modification sites, cell types and disease stages. We distinguish relatively developed experimental evidence in acute ischemic stroke and cerebral ischemia-reperfusion injury from limited findings in haemorrhage and predominantly exploratory evidence in chronic hypoperfusion and vascular cognitive impairment. Proteomic studies have identified 1003 lactylation sites across 469 proteins in rats subjected to cerebral ischemia-reperfusion injury, although most sites have not undergone causal validation. Comparatively strong evidence has accumulated for sites or regulatory axes involving MeCP2, SOD2, NEK7, ACSL4, PLBD1 and ZO-1. Collectively, current findings indicate that the effects of a given acylation cannot be inferred from its global abundance because they depend on substrate function, cellular origin and the therapeutic window. Major limitations include insufficient site-specific causal evidence, difficulty in directly quantifying crosstalk among post-translational modifications, poor correspondence between animal models and clinical heterogeneity and the absence of effective delivery systems and pharmacodynamic biomarkers. Future studies should integrate spatiotemporally resolved multi-omics, endogenous site editing, cell-specific models, measurable target engagement and independent clinical cohorts to evaluate whether selected acylation sites can progress from experimental candidates to independently validated clinical markers or intervention targets.