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.