AIM: To investigate the causal effects of ceramides on retinal vein occlusion(RVO)and elucidate their potential mediating mechanisms using Mendelian randomization(MR)analysis.

METHODS: Genome-wide association study(GWAS)data for four ceramide species were utilized 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(95% CI): 0.750(0.604-0.930), P<0.05\〗 and ceramide(d42:2)\〖IVW OR(95% CI): 0.771(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. Similarly, ceramide(d42:2)acted via N-methylhydroxyproline, the same fatty acid group, N1-methyladenosine, and the leucine-to-N-palmitoyl-sarcosinate ratio.

CONCLUSION: Ceramides(d40:1)and(d42:2)confer protection against RVO, partially mediated by specific metabolic pathways.