Identifying the Potential Diagnostic Gene Biomarkers and Forecasting the Potential Therapeutic Agents for Advanced Diabetic Nephropathy Based on Pyroptosis and Ferroptosis.

BACKGROUND

Diabetic nephropathy (DN) is a prevalent complication of diabetes, often leading to end-stage kidney disease (ESKD). Advanced DN progresses to ESKD rapidly, yet effective diagnostic indicators and treatments are lacking.

METHODS

Two DN-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the R packages. Pyroptosis-related genes (PRGs) and ferroptosis-related genes (FRGs) were collected from their respective database. Pyroptosis- and ferroptosis-related differentially expressed genes (PFRDEGs) were identified by overlapping DEGs, PRGs, and FRGs for further analysis, including functional enrichment and immune infiltration. Hub genes were identified using a PPI network via MCODE-plugin in Cytoscape. GeneMANIA was utilized to explore intermolecular interactions among hub genes. Based on these hub genes, a diagnostic model was constructed using the receiver operating characteristic curve and potential therapeutic agents were retrieved. Correlation analysis between hub genes and estimated glomerular filtration rate was performed using Nephroseq v5 database, and expression of hub genes was validated in external GEO database, Nephroseq v5 database and DN mice in vivo.

RESULTS

Four hub genes (CYBB, LCN2, JUN and ADIPOQ) were identified, and three of the four hub genes (CYBB, LCN2 and ADIPOQ) were found to be potential biomarkers for advanced DN. On this basis, three potential therapeutic agents were screened. More importantly, a series of biological experiments confirmed that CYBB and LCN2 were significantly up-regulated in DN mice.

CONCLUSION

This study identifies three hub genes as diagnostic biomarkers and mines three potential therapeutic agents for advanced DN, providing new insights into the role of pyroptosis and ferroptosis in advanced DN and laying the foundation for future research.