Identification of novel therapeutic targets for diabetic neuropathy through integrated proteomics and transcriptomics...

Diabetic neuropathy (DN) is a progressive disorder with limited effective treatment options.

To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.

A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN. Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers. Tier 1 target proteins were further analyzed. Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins. The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization (MR) analysis.

Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data. BTN3A1 and MICB were confirmed using MR, summary data-based MR, and colocalization analyses. Of the nine, HSPA1B, PSMB9, BTN3A1, SCGN, NOTUM, and MICB showed negative associations with DN, whereas WARS, BRD2, and CSNK2B were positive. Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways. BTN3A1 and MICB were identified as Tier 1 targets. Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate. Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++ monocytes. These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.

Our integrated multi-omics approach identified two promising therapeutic targets for DN, laying the groundwork for new treatment strategies and enhancing our understanding of MICB's role in DN.