Integrative Transcriptomic Profiling Identifies TLR9 as a Key Biomarker of Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent complication of type 2 diabetes that is typically diagnosed after irreversible nerve damage, largely due to the lack of molecular biomarkers that distinguish neuropathy-specific changes from general diabetic pathology. From an integrative biology perspective, the network-level molecular mechanisms underlying DPN remain incompletely defined. In this study, transcriptomic profiles from peripheral blood mononuclear cells of healthy controls, patients with type 2 diabetes, and patients with DPN were analyzed using a systems-level, network-based bioinformatics framework. Comparative analysis identified genes specifically associated with DPN, distinct from broader diabetic alterations. Protein-protein interaction and network topology analyses prioritized key hub genes enriched in immune signaling, calcium transport, lipid metabolism, and inflammatory pathways implicated in neuronal dysfunction. Among these, Toll-like receptor 9 (TLR9) emerged as a prominent biomarker candidate, demonstrating high network centrality and strong diagnostic performance (area under the curve = 1.0). TLR9 was significantly upregulated in DPN and functionally linked to mitogen-activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B-cell signaling pathways, consistent with immune-mediated mechanisms of neuropathic injury. Collectively, these findings define a DPN-specific molecular network and support TLR9 as a biomarker candidate, providing a systems-level foundation for future experimental validation and translational research in diabetic neuropathy.