Multi-Omics Insights Into Circulating T-Cell Metabolic Reprogramming and Treg Dysfunction in Moyamoya Disease

Moyamoya disease (MMD) is a progressive cerebrovascular disease linked to immune dysregulation, yet T-cell metabolic reprogramming and regulatory T-cell (Treg) function remain poorly understood. Here, we integrated multi-omics approaches, including mass cytometry, single-cell RNA sequencing, bulk RNA sequencing, metabolomics, and flow cytometry to characterize T-cell metabolic alterations and Treg dysfunction in MMD, uncovering a key metabolic-immune axis. Compared with healthy controls, MMD patients showed chronic immune activation and broad suppression of amino acid, glycolytic, and fatty acid metabolic pathways. Although Tregs were aberrantly expanded, they displayed metabolic inflexibility, together with impaired intercellular communication. Single-cell transcriptomics indicated Treg-to-Th17 conversion, while flow cytometry confirmed increased IL-17A⁺ cells within the CD4⁺FOXP3⁺ compartment. Besides, these dysfunctional Tregs correlated with advanced Suzuki stages, ischemic stroke, and posterior cerebral artery involvement. Bulk transcriptomic and serum metabolomic analyses further confirmed coordinated immune activation and metabolic suppression at the gene, protein, pathway, and metabolite levels. These findings define a metabolic-immune axis in MMD in which metabolically constrained, functionally unstable Tregs may contribute to neuroinflammation and vascular remodeling, suggesting that restoring Treg metabolic fitness could represent a therapeutic strategy.