We explored the contribution of Damage-Associated Molecular Pattern (DAMP) proteins and the specific receptor Toll-like receptor 4 (TLR4) to the inflammatory and vascular dysfunction underlying DFS progression. Clinical, hematological, and proteomic analyses were performed on plasma of patients with diabetes without foot syndrome (D) and with DFS. Candidate plasma DAMPs were evaluated for their discriminatory capacity using ROC analysis. DFS patients exhibited systemic inflammation and hematologic imbalance, with a pronounced induction of acute-phase amyloid isoforms (SAA1, SAA2, APCS) and multiple fibrinogen isoforms. Up-regulation of stress-responsive extracellular matrix and adhesion molecules (FGL1, HSPA5, DEFA1B, S100A8, TNN, TMSB4X) was detected. In contrast, structural matrix proteins (FN1, TNXB) were down-regulated. ROC analysis identified these DAMPs (excluding FGL1) as strong discriminators between D and DFS patients. In vivo inhibition of TLR4 attenuated the regulation of amyloid isoforms.