Dysregulation of circulating damage-associated molecular patterns in diabetic foot syndrome.

Background: Diabetic foot syndrome (DFS) is characterized by chronic inflammation, thrombotic imbalance, and impaired wound healing, yet systemic molecular alterations underlying this complication remain incompletely defined. In this study, we combined clinical plasma proteomics with experimental pharmacological modulation to characterize a circulating damage-associated molecular pattern (DAMP)-related signature linked to systemic inflammatory signaling in DFS. Methods: Plasma samples from patients with type 2 diabetes with and without DFS, including individuals with varying degrees of limb ischemia, were analyzed using liquid chromatography-tandem mass spectrometry. Differentially abundant proteins were evaluated in relation to inflammatory, hematological, and metabolic parameters. Pharmacological responsiveness was assessed in a murine diabetic ischemic wound model treated with a selective Toll-like receptor 4 (TLR4) inhibitor. Results: Proteomic analysis identified coordinated differences in the abundance of multiple acute-phase and stress-associated proteins, including serum amyloid A1, serum amyloid A2, serum amyloid P component, S100A8, defensin alpha 1B, fibrinogen chains, heat shock protein family A member 5, thymosin beta 4, fibronectin 1, and tenascins. These proteins exhibited differences between DFS patients and diabetic controls and were explored in relation to systemic inflammatory variables. Several DAMPs demonstrated reproducible patterns across the studied groups, suggesting the presence of a coordinated circulating molecular pattern rather than isolated changes in individual proteins. In diabetic ischemic mice, TLR4 inhibition was associated with altered abundance of several circulating proteins, including reductions in selected amyloid-associated proteins. These observations suggest an association between modulation of innate immune signaling pathways and circulating protein profiles. Conclusion: Overall, these findings support a systemic alteration in circulating DAMP abundance in DFS and provide exploratory clinical and experimental evidence to guide future investigations into DAMP-mediated inflammatory pathways in diabetic ischemic complications. Proteomics data are available via ProteomeXchange with identifier PXD073507.