Combined proteomics and metabolomics analyses revealed molecular signatures associated with proliferative diabetic...

Diabetic retinopathy (DR) is a microvascular complication of diabetes with its exact underlying mechanisms have not been fully elucidated. This study aimed to investigate the effects of key proteins and metabolites on the development of DR. Undiluted vitreous fluid samples were collected from eight patients with proliferative diabetic retinopathy (PDR) and six non-diabetic idiopathic macular hole (iMH) controls. Integration of TMT-tagged quantitative proteomics and untargeted metabolomics analyses was combined with bioinformatics approaches (PCA, differential expression, PPI network, OPLS-DA, pathway enrichment). Key results were validated by ELISA, immunohistochemistry, and cell proliferation and migration assays. Seven key proteins with six key metabolites were identified to be significantly dysregulated in the PDR. In the vitreous body and retinal nerve fiber layer of the DR group, CD5L expression was upregulated, while CLU was downregulated with SERPINF1 (PEDF). CD5L markedly promotes the proliferation and migration of endothelial cells.These molecules were co-enriched in pathways such as the "complement and coagulation cascade" and "prion disease," suggesting a common mechanism of abnormal vascular permeability, inflammatory response, and microthrombosis. Disturbances in creatine metabolism suggested AMPK-related energy dysregulation, and the interaction between CD5L and microglia emphasized its neuroinflammatory regulatory function. This study revealing biomarkers and therapeutic targets, which provide new ideas for diagnosis and precise intervention.