ObjectiveTo explore the differences in metabolomic changes and metabolic pathways between the vitreous humor and serum of patients with early-onset proliferative diabetic retinopathy (PDR). MethodsA prospective observational study. From January to June 2025, 30 patients with PDR who underwent pars plana vitrectomy (PPV) in the Department of Ophthalmology, Peking University People's Hospital were included in the study. Patients were categorized into an early-onset PDR group (diagnosis age ≤40 years, n=10) and a late-onset PDR group (diagnosis age ＞40 years, n=20) based on the age at diabetes diagnosis. Fasting serum samples collected preoperatively and vitreous humor samples obtained intraoperatively were analyzed using untargeted metabolomics via ultra-high-performance liquid chromatography coupled with electrostatic field orbitrap tandem mass spectrometry. Differential metabolites were screened with thresholds of P＜0.05, variable importance in projection＞1, and fold change＞1.200 or ＜0.833. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG). The Mann-Whitney U test was used to compare clinical data between the two groups. ResultsSignificant differences were observed between the early-onset and late-onset PDR groups in the age at diabetes diagnosis and diabetes duration (Z=?4.41, ?2.62; P＜0.05). Metabolomic analysis identified 37 differential metabolites in the vitreous humor (34 upregulated, 3 downregulated) and 42 in the serum (10 upregulated, 32 downregulated). The two most abundant classes of differential metabolites common to both sample types were carboxylic acids and derivatives (16.2% in vitreous, 16.7% in serum) and fatty acyls (13.5% in vitreous, 11.9% in serum). KEGG enrichment analysis revealed the tryptophan metabolism pathway was significantly enriched in the vitreous humor (enrichment factor=0.024, P＜0.05), with L-kynurenine and indole-3-acetamide as key differential metabolites. In the serum, the taurine and hypotaurine metabolism pathway was significantly enriched (enrichment factor=0.042, P＜0.05), with hydroxyethanesulfonic acid identified as a differential metabolite. ConclusionsEarly-onset PDR has characteristic metabolic disorders. The dual activation of the kynurenine and indole branches of tryptophan metabolism in the vitreous humor, alongside increased consumption in the taurine pathway in serum, may underlie its pathophysiology. Additionally, abnormalities in serum steroids and steroid derivatives suggest that dysregulated steroid hormone metabolism might contribute to disease progression.
