Untargeted-metabolomics reveals size-dependent metabolic disparities of apical periodontitis lesions.

[AIM] This study aimed to investigate the variations in metabolic differences associated with the disease severity of apical periodontitis (AP) by comparing lesions of different sizes.

[METHODS] Twelve apical tissue samples were collected during apical microsurgery from patients without systemic diseases, comprising 6 large lesions (greater than 1000 mm³) and 6 small lesions (<1000 mm³). Liquid chromatography-mass spectrometry was conducted to analyze the metabolic profiles of AP lesions with different sizes. Principal component analysis and orthogonal partial least squares discriminant analysis were utilized to characterize lesion size-dependent metabolic disparities. Subsequently, differentially expressed metabolites (DEMs) screening and enrichment analysis was employed to clarify metabolic pathways that correlate with AP lesion size heterogeneity.

[RESULTS] Among the 2431 detected metabolites, 21 DEMs were identified. Large lesions exhibited the upregulation of 11 metabolites (e.g., α-linolenic acid, eicosatetraenoic acid), which were predominantly enriched in "α-linolenic acid metabolism" and "unsaturated fatty acid biosynthesis". Small lesions showed the upregulation of 10 metabolites (e.g., choline, 2'-deoxyinosine), which were enriched in pathways related to "purine metabolism", "glycine, serine and threonine metabolism", "glycerophospholipid metabolism" and "glutathione metabolism".

[CONCLUSION] There are distinct metabolic profiles characterize between different states of AP. Large lesions exhibited elevated levels of fatty acid derivatives, implicating enhanced unsaturated fatty acid biosynthesis. Conversely, small lesions showed upregulation of nitrogenous bases and amino acid derivatives, suggesting dysregulation in purine and glutathione-related pathways. The distinct metabolite profiles indicate their biomarker potential for disease severity and efficacy optimization.

[CLINICAL SIGNIFICANCE] The differential-expressed metabolites and pathways observed between large and small lesions suggests their potential role as biomarkers for as targets for further mechanistic investigation.