Integrated multi-omics identifies macrophage ARG1-mediated deacetylation with causal and diagnostic implications in ischemic stroke.

Ischemic stroke (IS) involves transcriptional dysregulation linked to epigenetic deacetylation. By integrating multi-omics data from IS patients and an MCAO model, we identified fifty-two differentially expressed deacetylation-related genes (DEARGs) and derived a three-gene signature (VIM, ARG1, and PRPF31) that exhibited high diagnostic accuracy (AUC = 0.840) and stratified IS patients into two immunologically distinct molecular subtypes with divergent immune microenvironment infiltration patterns. Two-sample Mendelian randomization analysis with 24 eQTL-derived instrumental variables confirmed ARG1 as a causal factor for IS (IVW method; FDR-corrected p = 0.03). Single-cell RNA sequencing validated specific ARG1 upregulation in infiltrating macrophages of a mouse MCAO model and myeloid subsets of human IS PBMCs, with RT-qPCR further verifying this pattern. Together, our study links this deacetylation-associated signature to immune heterogeneity in IS, identifies ARG1-expressing myeloid cells as potential mediators of epigenetic immune dysregulation, and provides a framework for stratified therapeutics.