EXPRESS: Infection, Inflammation, and the Second Hit Hypothesis in Moyamoya Disease: A Comprehensive Review

BACKGROUND: Moyamoya disease (MMD) is a progressive cerebrovascular disorder with significant morbidity. RNF213 is the primary susceptibility gene, but its low penetrance suggests a "second hit" (e.g., infection/inflammation) is required for clinical onset. This review synthesizes evidence on RNF213's immunological functions and downstream cascades driving MMD arteriopathy, identifying translational opportunities and knowledge gaps. METHODS: We performed a narrative synthesis of peer-reviewed literature (PubMed, Web of Science, Scopus, up to 2026) on RNF213 biology, immune-inflammatory signaling, endothelial dysfunction, angiogenesis, and animal models, constructing a mechanistic framework linking genetics to environmental triggers. RESULTS: RNF213 modulates interferon and NF-κB pathways. MMD arteriopathy results from endothelial dysfunction, aberrant angiogenesis, and chronic perivascular inflammation, converging on smooth muscle proliferation and stenosis. Translational tools-circulating biomarkers and immunomodulators-show preliminary promise but remain exploratory. CONCLUSION: Evidence supports an immune-mediated two-hit model, but the spatiotemporal sequence from peripheral triggers to focal intracranial disease is unresolved. Major limitations include lacking robust animal models and prospective biomarker validation. Future research should prioritize longitudinal multi-omics, patient-derived iPSC models, and validated biomarker cohorts to enable precision medicine.