颅内出血(intracerebral hemorrhage，ICH)是一种高致死率的卒中类型，其核心病理机制涉及脑血管稳态受损。遗传因素在ICH疾病发生中占据重要地位，因此挖掘关键调控因子、完善ICH的病理机制网络尤为重要。本研究通过全基因组关联分析，筛选到与ICH显著相关的遗传易感基因——突触足蛋白(synaptopodin)编码基因SYNPO。既往研究表明，SYNPO作为一种进化保守的肌动蛋白结合蛋白，在脑血管内皮细胞中高表达，通过调控肌动蛋白骨架维持内皮细胞连接稳态。然而，其在ICH中的具体作用尚不明确。为此，本研究进一步利用CRISPR/Cas9技术构建了synpo突变体斑马鱼。在肾上腺素刺激下，synpo突变体幼鱼脑血管渗漏率和成鱼ICH发生率都显著高于野生型。转录组分析发现，synpo突变体脑内细胞黏附通路关键基因cdh2显著下调，回补cdh2 mRNA可有效挽救突变体幼鱼的脑血管渗漏。本研究揭示了synpo通过正向调控cdh2维持脑血管稳态，明确“synpo-cdh2”轴是ICH的关键调控通路，为解析ICH的遗传机制及发现潜在干预靶点提供新视角。

Intracerebral Hemorrhage (ICH) is a stroke subtype with high mortality, and its core pathological mechanism involves the disruption of cerebrovascular homeostasis. Genetic factors play a crucial role in ICH pathogenesis, underscoring the importance of identifying core regulatory factors and delineating the associated pathological network. Here, through genome-wide association study (GWAS), we identified synaptopodin (SYNPO) as a genetic susceptibility gene for ICH. SYNPO is an evolutionarily conserved actin-binding protein previously shown to be highly expressed in cerebrovascular endothelial cells, where it regulates the actin cytoskeleton to maintain endothelial junction stability. However, its functional role in ICH remains unclear. To investigate this, we conducted a synpo mutant zebrafish line using CRISPR/Cas9. Following epinephrine challenge, synpo mutant larvae displayed significantly elevated cerebrovascular leakage compared with wild-type controls, and adult mutants showed a markedly higher incidence of ICH. Transcriptomic profiling revealed significant downregulation of the key adhesion gene cdh2 in mutant brains. Subsequent rescue experiments confirmed that cdh2 mRNA supplementation effectively ameliorated the cerebrovascular leakage. In summary, our study unveils a pathway in which synpo maintains cerebrovascular homeostasis by positively regulating cdh2, demonstrating that the synpo-cdh2 axis serves as a key regulatory pathway in ICH. These findings provide insights into the genetic mechanisms underlying ICH and highlight potential therapeutic targets.