In this study, we leveraged 15 paired plasma samples collected from the same individuals who exhibited rapid progression from DM to DR within 1-2 years and conducted integrated proteomic and metabolomic analyses to investigate molecular changes associated with disease progression. Key proteins were validated by ELISA in an independent cohort of 22 DM and 22 NPDR patients and their predictive performance was assessed using receiver operating characteristic (ROC) curve analysis. The results revealed significant alterations at both the protein and metabolite levels during the progression from DM to DR. Among the validated proteins, three ((ANXA1, GPX1, and GSTM1) were previously reported in DR, while five (ALDH18A1, GALT, PRG2, UBA1, and GCA) represent newly identified candidates. ROC analysis demonstrated strong discriminative performance for these proteins, with area under the curve (AUC) values ranging from 0.853 to 0.945. These findings provide insight into the molecular mechanisms underlying early DR progre