Uncovering the metabolic-epigenetic links between gene expression and stroke: insights from lactylation pathway MR study

Lactylation, a novel post-translational modification driven by lactate accumulation, has been implicated in neuroinflammation and metabolic stress. However, its causal relevance to ischemic stroke (IS) and its subtypes—large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS)—remains unknown. We conducted a two-sample Mendelian randomization (TSMR) analysis to investigate the causal relationships between lactylation-associated gene expression and IS risk. Lactylation-related genes were identified from a recent literature review and intersected with eQTL data from the eQTLGen Consortium (n = 31,684). Summary statistics for IS and its subtypes were obtained from large-scale GWAS (total cases = 62,100; controls = 1,234,808). Primary analyses used the inverse-variance weighted (IVW) method, complemented by MR-Egger, weighted median, and sensitivity tests to assess heterogeneity and pleiotropy. A total of 15 genes and 274 single nucleotide polymorphisms (SNPs) were included. Elevated expression of SIRT1, SMARCA4, STMN1, and LDHA was significantly associated with increased risk of IS or its subtypes. In contrast, SLC16A1, SIRT3, PFKP, and TKT were inversely associated with stroke risk, suggesting a potential protective role. Most associations were robust across multiple MR models. Pleiotropy and heterogeneity were observed for SMARCA4 in LAS. This study provides genetic evidence for the involvement of lactylation-related genes in IS pathogenesis, revealing novel risk-enhancing and protective factors. These findings enhance our understanding of metabolic-epigenetic mechanisms in stroke and suggest potential molecular targets for future interventions.