CD163 and TYROBP Are Two Therapeutic Targets for Hyperglycemia‐Induced Mesangial Cell Stress

ABSTRACT Diabetic nephropathy (DN) is a severe microvascular complication of diabetes. This study aimed to identify hub genes and explore potential therapeutic drugs for DN. Differentially expressed genes were analyzed between DN and normal samples from the GSE104948 and GSE47183 datasets. Hub genes were identified through weighted gene coexpression network analysis and protein–protein interaction network analysis and validated using two external datasets. Receiver operating characteristic curves were employed to assess the diagnostic accuracy of the hub genes. Virtual screening identified potential small‐molecule compounds targeting the hub genes CD163 and transmembrane immune signaling adaptor TYROBP (TYROBP). High‐glucose (HG)‐induced human glomerular mesangial cells (HGMCs) were used to construct an in vitro DN model. Cell viability was assessed using a cell counting kit‐8, and inflammatory factors were measured by enzyme‐linked immunosorbent assay, and mesangial extracellular matrix‐related protein levels were detected by Western blot. Two hub genes, CD163 and TYROBP, were identified as significantly upregulated in DN samples and HG‐induced HGMCs, demonstrating high specificity and sensitivity for DN diagnosis. Demethyleneberberine (DMB) and dehydroevodiamine (DHE) exhibited strong binding affinity to CD163 and TYROBP and effectively suppressed HG‐induced HGMC proliferation, inflammatory responses, and extracellular matrix deposition. In conclusion, CD163 and TYROBP serve as key biomarkers and therapeutic targets for DN, while DMB and DHE show promise as natural compounds for DN treatment.