Integrated Transcriptomic and Secretome Proteomic Analysis of Hyperglycemia-Stimulated Endothelial Cells and Screening of Target Compounds

Endothelial dysfunction is a key driver of diabetic kidney disease (DKD), but its systemic molecular mechanisms remain incompletely decoded. We hypothesized that integrated multi-omics analysis could map hyperglycemia-induced endothelial damage and identify reusable therapeutics. A reusable computational pipeline was applied to integrate transcriptomic/secretome profiles from hyperglycemic endothelial cells and diabetic kidneys. This identified 534 commonly upregulated genes/proteins. Functional enrichment revealed activation of extracellular matrix remodeling, intercellular communication, and inflammation pathways. Cross-database validation refined 278 high-confidence mediators, and protein-protein interaction network analysis pinpointed ten hub genes. Using network pharmacology, we screened an approved drug library, identifying several candidate compounds (e.g., bruceantin, idelalisib) that potentially target this network. Furthermore, transcription factor regulation and exemplary molecular docking simulations (e.g., idelalisib with CTCF/BRD4) provided mechanistic hypotheses for experimental validation. In conclusion, this study establishes a reusable multi-omics framework that delineates endothelial pathogenic mechanisms in DKD and nominates repurposable drug candidates, offering a strategic approach for mechanistic and therapeutic discovery.