Integrated Serum Multiomics Reveal Subtype‐Specific Immune Dysregulation and Sex‐Dimorphic Pathophysiology in Moyamoya Disease

BACKGROUND: Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown pathogenesis, partly due to limited access to human cerebral vascular tissue and suitable animal models. Using a large biobank of frozen serum samples, this study aimed to explore molecular signatures of ischemic and hemorrhagic MMD. METHODS: Serum from 30 patients with MMD (18 ischemic, 12 hemorrhagic) and 30 matched healthy controls underwent proteomic and metabolomic profiling. Data were analyzed for differential expression, pathway enrichment, and protein-metabolite networks, with adjustment for age, sex, and body mass index. RESULTS: <0.05). At the molecular level, ischemic MMD showed complement C4-B deficiency and disrupted natural killer cell cytotoxicity; both subtypes shared immunoglobulin perturbations (eg, decreased heavy-chain variable regions). Sex-specific alterations included anti-folate-binding protein, serum amyloid A2, glycolithocholic acid, and estradiol. All omics data are publicly accessible. CONCLUSIONS: Integrated serum multiomics defines distinct immune-related signatures for ischemic and hemorrhagic MMD and reveals sex-dimorphic molecular pathways. These findings, together with clinical sex differences in disease subtype and vascular anatomy, provide a framework for personalized, sex-aware management of MMD.