Exploring the toxicological network in diabetic microvascular disease

Purpose: This study investigates how endocrine-disrupting chemicals contribute to diabetic microvascular disease. Methods: This study assessed endocrine-disrupting chemical toxicity using PubChem, ProTox 3.0, and ChEMBL. Relevant EDC targets were identified via SwissTargetPrediction and Similarity Ensemble Approach. Gene targets for diabetic microvascular diseases (diabetic kidney disease, retinopathy, and sensory polyneuropathy) were retrieved from CTD, GeneCards, and OMIM. Candidate targets were identified by intersecting EDC and disease-related targets. A protein-protein interaction network was built using STRING to identify hub genes. Functional enrichment analysis was conducted via Metascape. Molecular docking of EDC compounds with hub targets was performed using Discovery Studio and CDOCKER. Hub targets were validated through immunohistochemical staining, single-cell distribution, subcellular localization assays, and gene expression analysis in external HPA and GEO datasets. Results: A total of 843, 474, and 623 potential toxic targets were identified for diabetic kidney disease, diabetic retinopathy, and diabetic sensory polyneuropathy, respectively. KEGG pathway analysis linked EDC toxicity in diabetic kidney disease to key pathways such as cancer, chemokine signaling, apoptosis, calcium signaling, and drug metabolism (cytochrome P450), with hub targets including EGFR, ALB, MYC, ESR1, and HSP90AA1. Diabetic retinopathy was associated with MAPK, ERBB, NOD-like receptor signaling, and renal cell carcinoma pathways, with ALB, EGFR, MYC, BCL2, and CD4 identified as hub targets. For diabetic sensory polyneuropathy, EDCs may influence chemokine, apoptosis, ERBB, VEGF, and JAK-STAT signaling pathways, with ALB, EGFR, MYC, ESR1, and BCL2 as key targets. Molecular docking confirmed strong binding activity between EDC components and hub targets. Conclusion: This study offers a theoretical basis for identifying toxic targets and mechanisms by which endocrine-disrupting chemicals contribute to diabetic microvascular diseases.