5′-methylthioadenosine modifies the association between homocysteine metabolism and ischemic stroke: a nested case–control study

This study aimed to elucidate the interrelationships among 5′-Methylthioadenosine (MTA), Homocysteine (Hcy), and ischemic stroke (IS) and to examine the mediating role of MTA via Hcy metabolism, with the ultimate goal of informing stroke prevention strategies and guiding further research. This study was based on cohorts established through a hypertension health management program and a comprehensive stroke prevention project for high-risk participants at community health centers. Basic demographic information was collected via questionnaires and physical examinations. A nested case–control study was designed, comprising 148 participants with IS as the case group and 148 non-IS individuals as controls. Plasma concentrations of MTA, Hcy, and other metabolites were measured using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The association between MTA levels and IS was analyzed using a restricted cubic spline (RCS) model. Furthermore, structural equation modeling (SEM) was performed with AMOS 24.0 to assess the mediating effect of MTA on IS through Hcy. A significant inverse correlation was observed between MTA levels and the risk of IS ( p < 0.05), whereas Hcy levels were positively associated with stroke risk ( p < 0.05). The restricted cubic spline model revealed a non-linear relationship between MTA and IS risk. Restricted cubic spline analysis suggested a non-linear, J-shaped association between MTA levels and the risk of IS. Mediation analysis further demonstrated a significant direct effect of MTA on reducing IS risk ( ADE = − 0.0172, p < 0.001). In addition, Hcy exerted a significant indirect effect in the MTA-IS relationship ( ACME = − 0.0449, p < 0.001), indicating a statistically significant mediating role of Hcy. MTA served as a protective factor against IS, partly through its association with Hcy concentrations. These findings suggested that MTA may represent a novel biomarker for risk assessment and prevention of IS.