Therapeutic targets for diabetic nephropathy identified by druggable genome mendelian randomization: the role of the gut microbiota-metabolite axis

Background Diabetic nephropathy (DN), a severe complication of diabetes, is influenced by genetic, immune, and gut microbial factors but lacks targeted therapeutic strategies. Druggable genes (DGGs) present a promising avenue, yet their causal prioritization in DN and their connections to gut microbiota-metabolite mechanisms remain underexplored. Methods This study utilized differential expression analysis to identify differentially expressed genes (DEGs), Mendelian randomization (MR) to establish causal associations with DN, and machine learning algorithms to pinpoint key genes. Blood samples were subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for preliminary validation. Further validation incorporated nomogram modeling, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, molecular docking, and single-cell RNA sequencing (scRNA-seq), which included pseudotime trajectory and cell communication analysis. Results A total of 8,913 DEGs were identified, with MR analysis revealing 1,263 genes potentially involved in DN pathogenesis and as drug targets. FOS and IL12A were selected as potential key genes, both of which were significantly downregulated in DN and validated via RT-qPCR ( p 0.05). The predictive nomogram model achieved an area under the curve (AUC) greater than 0.7. Functional enrichment analysis highlighted the mTOR complex 1 (mTORC1) signaling pathway. FOS expression correlated positively with neutrophil infiltration (r = 0.856, p 0.05), while IL12A inversely correlated with M2 macrophage infiltration (r = –0.377, p 0.05). Molecular docking revealed that FOS and IL12A may stably bind to butyrate (binding energies: –7.3 and –7.0 kcal/mol, respectively), and IL12A also binds to trimethylamine (binding energy: –6.4 kcal/mol). These findings were corroborated by preliminary associations with gut microbes such as Faecalibacterium prausnitzii and Lactobacillus acidophilus. scRNA-seq preliminary analysis identified proximal convoluted tubule cell 1 (PCT1) as a central cell type, exhibiting altered cell communication and differentiation trajectories, where FOS expression showed dynamic changes and IL12A remained persistently downregulated. Conclusion This druggable gene-oriented MR strategy preliminary nominates FOS and IL12A as potential therapeutic targets for DN. Their involvement in DN pathogenesis is mediated via mTORC1 signaling, PCT1 cellular reprogramming, immune microenvironment remodeling, and interactions with a gut microbiota-metabolite axis, laying the groundwork for targeted therapies and microecological interventions in DN.