Circulating acidic α-glucosidase as a potential biomarker for lactate-related immunometabolism in ischemic stroke.

BACKGROUND: The role of lactate metabolism in ischemic stroke (IS) remains incompletely understood. This study aimed to characterize lactate-related transcriptomic profiles in IS to identify novel diagnostic biomarkers. METHODS: Gene co-expression network analysis and machine learning were used to identify core lactate metabolism-related genes from public transcriptomic datasets and validate them in an independent clinical cohort. Single-cell mouse brain transcriptomic data further characterized GAA expression across brain cell types. An in vitro OGD/R model was established in GAA-high-expressing cells to assess its expression under ischemic/hypoxic conditions. GAA expression in immune cells and its association with macrophage polarization were also evaluated. RESULTS: GAA emerged as a core gene, exhibiting significant upregulation in the whole blood of IS patients with robust diagnostic performance (area under the curve = 0.873). This upregulation was confirmed in validation models. After stroke, GAA exhibited a cell-type-specific expression pattern: it was elevated in macrophages and microglia. Notably, GAA expression positively correlated with the anti-inflammatory M2 macrophage marker MRC1 (r = 0.43) and negatively correlated with the pro-inflammatory cytokine interleukin-1β (IL-1β) (r = -0.48), indicating that high GAA levels favor M2-biased polarization. CONCLUSION: GAA acts as a potential upstream regulator of lactate metabolism in IS. By linking lysosomal glycogen metabolism to lactate production, GAA may modulate macrophage polarization via a "lactate timer" mechanism. These findings highlight GAA as a promising blood-based biomarker for the auxiliary diagnosis of IS.