Mass spectrometry-based salivary lipidomics as a potential approach in glycemic dysregulation research and monitoring: a perspective review

Type 2 diabetes (T2D) and prediabetes (preT2D) represent major global health challenges and are closely associated with dyslipidemia and metabolic dysfunction. While blood-based lipidomics has provided valuable insights into pathogenic mechanisms and patient stratification, saliva is emerging as a promising alternative biofluid for non-invasive biomarker discovery. This critical perspective review explores the potential of mass spectrometry (MS)-based lipidomic approaches, which offer high molecular specificity, structural resolution, and sensitivity, for investigating and monitoring glycemic dysregulation through salivary lipid profiling. We first summarize evidence on blood lipidomic signatures associated with T2D and preT2D and then discuss the methodological advantages and analytical challenges of salivomics. Furthermore, we examine emerging MSbased comparative studies that demonstrate partial concordance between salivary and circulating lipid profiles, supporting both the technical feasibility and the translational potential of salivary lipidomics, provided that the specific pre-analytical and analytical challenges of salivary lipid analysis are systematically controlled through dedicated workflow optimization. Despite this encouraging framework, a significant knowledge gap remains, as MS-based salivary lipidomics has not yet been systematically applied to dysglycemic populations. Future research should prioritize: i) large-scale, multicenter, clinically well-characterized cohorts; ii) rigorous pre-analytical and analytical standardization; iii) comprehensive cross-biofluid comparisons. Finally, we discuss the prospective integration of validated salivary lipid biomarkers into lab-on-chip platforms for decentralized, cost-effective, and near-real-time diabetes monitoring, although substantial technological and translational challenges remain.