目的：使用孟德尔随机化研究的方法探究神经酰胺对视网膜静脉阻塞（Retinal vein occlusion, RVO）的作用以及其中介调控关系。方法：选取4种神经酰胺全基因组关联研究（Genome-wide association studies，GWAS）数据为暴露，选取芬兰数据库中RVO的GWAS数据为结局，研究其因果关系。此外，选取1400种代谢产物的GWAS数据为带选择的中介因子，研究暴露到结局的中介作用。结果：神经酰胺（d40:1）（IVW OR(95%CI):0.750(0.604-0.930),P<0.05）和神经酰胺（d42:2）（IVW OR(95%CI):0.771(0.632-0.941),P<0.05）与RVO有因果关联。神经酰胺（d40:1）通过介导3-甲基黄嘌呤（3-methylxanthine）、支链或直链或环丙基 10:1 脂肪酸（Branched-chain, straight-chain, or cyclopropyl 10:1 fatty acid）、谷氨酰胺（Glutamine）、羟基棕榈酰基鞘磷脂 (d181160(OH))（Hydroxypalmitoyl sphingomyelin (d181160(OH))）调控RVO的发生。神经酰胺（d42:2）通过介导N-甲基羟脯氨酸（N-methylhydroxyproline）、支链或直链或环丙基 10:1 脂肪酸（Branched-chain, straight-chain, or cyclopropyl 10:1 fatty acid）、N1-甲基腺苷（N1-methyladenosine）、亮氨酸与 N-棕榈酰肌氨酸（d18:1-16:0）的比率（Leucine to N-palmitoyl-sphingosine (d18:1-16:0) ratio）调控RVO的发生。结论：神经酰胺（d40:1）和神经酰胺（d42:2）对RVO具有保护作用，其通过调控多种中介因子作用与RVO。

Objective This study aimed to investigate the causal effects of ceramides on retinal vein occlusion (RVO) and elucidate their potential mediating mechanisms using Mendelian randomization (MR) analysis. Methods We employed a two-sample MR approach, utilizing genome-wide association study (GWAS) data for four ceramide species as exposures and RVO GWAS data from the FinnGen database as the outcome. Additionally, GWAS data for 1,400 intermediate metabolites were analyzed to identify potential mediators in the ceramide-RVO pathway. Results Two ceramide species exhibited significant causal associations with RVO: ceramide (d40:1) (IVW OR: 0.750, 95% CI: 0.604–0.930;?P?< 0.05) and ceramide (d42:2) (IVW OR: 0.771, 95% CI: 0.632–0.941;?P?< 0.05), suggesting protective effects. Mediation analysis revealed that ceramide (d40:1) influenced RVO risk through metabolites including 3-methylxanthine, branched/straight-chain/cyclopropyl 10:1 fatty acids, glutamine, and hydroxypalmitoyl sphingomyelin (d18:1/16:0(OH)). Similarly, ceramide (d42:2) acted via N-methylhydroxyproline, the same fatty acid group, N1-methyladenosine, and the leucine-to-N-palmitoyl-sphingosine (d18:1-16:0) ratio. Conclusion Our findings demonstrate that ceramide (d40:1) and (d42:2) confer protection against RVO, partially mediated by specific metabolic pathways. These results highlight novel mechanistic insights into ceramide-related metabolic regulation in RVO pathogenesis. Keywords ceramide; Mendelian randomization; retinal vein occlusion; metabolites; mediation analysis