Objective:

To identify druggable therapeutic targets for diabetic nephropathy (DN) through Mendelian randomization and explore their connections to gut microbiota and metabolites, emphasizing the significance of these connections.

Key Findings:

• Identified 8,913 DEGs with 1,263 genes potentially involved in DN pathogenesis.
• FOS and IL12A were selected as key genes, both significantly downregulated in DN.
• The predictive nomogram model achieved an AUC greater than 0.7.
• FOS expression positively correlated with neutrophil infiltration (r = 0.856), while IL12A inversely correlated with M2 macrophage infiltration (r = -0.377).
• Molecular docking indicated stable binding of FOS and IL12A to butyrate and trimethylamine.

Interpretation:

FOS and IL12A are potential therapeutic targets for DN, with their roles mediated through mTORC1 signaling and interactions with gut microbiota metabolites, suggesting implications for future research.

Limitations:

• Preliminary nature of findings requires further validation.
• Potential confounding factors, such as specific environmental influences, not fully addressed in the study.

Conclusion:

This study highlights FOS and IL12A as promising druggable targets for DN, suggesting a novel approach for targeted therapies and interventions that could significantly impact clinical practice.