Abstract
INTRODUCTION: Brain arteriovenous malformation (bAVM) rupture is a leading cause of hemorrhagic stroke in young adults, yet clinical predictors alone inadequately stratify rupture risk. Emerging evidence suggests that specific molecular and genetic factors may influence vessel wall integrity and hemorrhage susceptibility. This systematic review and meta‐analysis aim to identify and quantify key molecular and genetic markers associated with increased risk of bAVM rupture. METHODS: A comprehensive search was performed across PubMed, Embase, Scopus, and Cochrane databases through December 2024, following PRISMA guidelines. Eligible studies reported associations between molecular/genetic markers and bAVM rupture risk in human subjects. Data were extracted on inflammatory cytokines, angiogenic factors, proteolytic enzymes, and relevant signaling pathways. Meta‐analyses were conducted using random‐effects models in R. Heterogeneity was assessed using the I(2) statistic, and publication bias was evaluated through Egger's test and funnel plots. RESULTS: Thirty‐one studies met inclusion criteria, encompassing 1,986 patients. The most consistently upregulated biomarkers in ruptured bAVMs included inflammatory cytokines IL‐6 (OR 2.5, 95% CI: 1.6‐3.9), IL‐1β (OR 3.1, CI: 2.0‐4.8), and IL‐17A (OR 2.7, CI: 1.8‐4.0), suggesting a robust pro‐inflammatory milieu preceding hemorrhage. TNF‐α (OR 2.3, CI: 1.5‐3.6) was also significantly elevated, consistent with endothelial dysfunction. Elevated VEGF‐α (OR 2.9, CI: 1.9‐4.4) and matrix metalloproteinase‐9 (MMP‐9) (OR 3.4, CI: 2.3‐5.1) implicated pathological angiogenesis and extracellular matrix degradation, respectively. Additionally, activation of the NOTCH signaling pathway (OR 2.6, CI: 1.7‐3.9) was recurrently reported in ruptured specimens. Subgroup analyses showed higher effect sizes in younger patients and Spetzler‐Martin grade I‐II lesions. Heterogeneity across studies was moderate (mean I(2) = 41%), and sensitivity analyses confirmed the robustness of associations. CONCLUSION: This meta‐analysis highlights a converging inflammatory‐angiogenic molecular signature underlying bAVM rupture. Elevations in IL‐6, IL‐1β, TNF‐α, VEGF‐α, and MMP‐9—along with NOTCH pathway activation—demonstrate reproducible associations with hemorrhage risk. These markers provide a promising foundation for biologically informed risk stratification and open the door for future therapeutic targets, including anti‐inflammatory or anti‐angiogenic interventions. Future longitudinal and mechanistic studies integrating genomics and imaging are warranted to translate these findings into precision‐medicine approaches for bAVM management. [Image: see text]