Proteomic and Metabolomic Profiling in Moyamoya Disease: A Systematic Review

Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by stenosis and occlusion of the internal carotid artery branches, leading to chronic ischemia and aberrant collateral vessel formation. Despite its clinical significance, the pathophysiology is not fully understood, and identification of MMD-related biomarkers may supplement invasive digital subtraction angiography, the current gold standard for diagnosis, as well as provide additional insights into prognosis and disease progression. High-throughput metabolomics and proteomics offer potential to elucidate disease mechanisms and identify diagnostic markers. Our goal is to systematically review the current literature on metabolomics and proteomics in MMD using high-throughput methods, identify candidate biomarkers, characterize implicated pathways, and assess the diagnostic and prognostic value of molecular signatures. We searched PubMed, Embase, Web of Science, and Scopus databases through April 13, 2026, for studies analyzing serum or CSF from MMD patients using mass spectrometry, nuclear magnetic resonance, or immunoassays. Studies were included if they employed case-control, cohort, cross-sectional, or RCT designs in human subjects. Two reviewers independently screened titles, abstracts, and full texts, with disputes resolved by a third reviewer. Quality was assessed using the Newcastle-Ottawa Scale. We extracted the top differentially expressed proteins or metabolites, results of any enrichment pathway analyses, and demographics information from each study. From 3071 studies identified, 31 were included after removing 1558 duplicates and excluding 1482 irrelevant studies. Recurrent differentially expressed proteins implicated inflammatory signaling (CRABP-I, PDGF-BB, IL-7, complement proteins), angiogenesis (VEGF, Ang-2, MMP-9), and cytoskeletal remodeling (FLNA, ZYX, keratins), while consistent metabolomic signatures highlighted BCAA elevation, urea cycle disruption, and lipid remodeling. Pathway analyses recurrently implicated immune activation, endothelial dysfunction, cytoskeletal reorganization, hypoxia signaling, and metabolic reprogramming. Demographically, cohorts were predominantly adult, East Asian, and bilateral MMD, with a sample-size-weighted mean age of 40.0 years. High-throughput proteomics and metabolomics identified recurring molecular alterations in Moyamoya disease, commonly identifying inflammatory signaling, pathological angiogenesis, and cytoskeletal remodeling as potential pathophysiological mechanisms. Despite predominantly good-quality studies (mean Newcastle-Ottawa Scale 6.77 ± 0.67), major limitations included small sample sizes, single-center designs, and regional specificity. Validation in larger, ethnically diverse, multicenter cohorts is essential before clinical translation of candidate biomarkers and therapeutic targets.