Structural Peptidomics of Diabetic Saliva Reveals Mucosal Barrier Remodeling and Design Cues for Biofabrication

Saliva provides a non-invasive window into systemic health; however, most diabetes-related omics research focuses on whole proteins rather than the structural information contained in endogenous peptides. The human salivary peptidome was characterised in individuals with type 2 diabetes (T2D) compared to normoglycaemic controls using a peptide-centred, library-free DIA-NN approach. A total of 199 significantly modulated peptides (|FC| ≥ 1.5; p < 0.05) were identified, showing a marked asymmetry pattern with increased levels of apolipoprotein, complement, mucin, and haemoglobin fragments in T2D. These changes reflect coordinated adjustments in mucosal barrier regeneration, lipid metabolism, and microvascular permeability. AlphaFold modelling of representative peptides revealed distinct structural motifs – flexible mucin loops, amphipathic helices, and redox-active globin segments – suggesting roles in hydration, immune regulation, and hydrogel behaviour. These results show that salivary peptides are structurally and functionally relevant indicators that surpass conventional protein-level analysis. This study combines deep peptidomics with structure prediction to clarify molecular changes in the diabetic salivary environment and establishes a framework for using endogenous peptides as both diagnostics and functional components for mucosa-inspired bioinks in tissue engineering.