Introduction: Diabetic nephropathy, retinopathy, and neuropathy are interconnected microvascular complications of diabetes, often co-occurring due to shared underlying mechanisms of damage from chronic hyperglycemia. Increased severity of one complication frequently correlates with increased severity of the others. Protein interactions play a crucial role in the development and progression of systemic diseases. Aberrant protein-protein interactions (PPIs) can disrupt normal cellular processes. Therefore, this study aimed to identify the relationship between neuropathy, nephropathy, and retinopathy and explore overlapping mechanisms, with a focus on improving therapeutic strategies.
Methods: Public databases were used to retrieve genes associated with diabetic nephropathy, retinopathy, and neuropathy. To find the key targets, the protein interactions of the common genes between the diabetic complications were retrieved from the STRING database (https://string-db.org/). The PPI network was built and analyzed using Cytoscape software. The CytoHubba plugin was employed to identify hub proteins using the MCC analysis method. Drug-gene interactions were obtained from DGIdb (https://dgidb.org/). Network pharmacology and molecular docking technology were used to screen and verify potential candidate drug-protein interactions.
Results: IFNG, IL10, CXCL10, CCL5, IL1A, CCL2, TNF, IL1B, CXCL8, IL6 were identified as hub proteins. 208 drug-target interactions were extracted. Pentoxifylline was identified as a drug with the most target interactions. Molecular docking analysis indicated that the interaction of IL1B and TNF with pentoxifylline is strong (-6.25 kcal/mol and -5.45 kcal/mol), while the interaction of CXCL8 with pentoxifylline is moderate (-4.82 kcal/mol).
Conclusion: These findings highlight the role of hub protein-mediated interactions in the underlying mechanisms and therapeutic targets of systemic diseases.
Keywords: Diabetic complications, Protein interaction network, Network pharmacology, Molecular Docking