Objective ·To investigate the salivary metabolic characteristics of periodontitis patients with chronic renal failure (CRF) and analyze the role of phosphorus metabolites in this pathological process. Methods ·A total of 45 patients treated at the Department of Nephrology and the Department of Periodontology, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine were enrolled, including 15 patients with both periodontitis and CRF in the CRF group, 15 with only periodontitis in the periodontitis (CP) group, and 15 in the healthy control (HC) group. All participants underwent unstimulated saliva collection and periodontal clinical examination. Periodontal clinical parameters were recorded, and renal function indicators of patients in the CRF group were documented. Untargeted metabolomic analysis of saliva samples was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis (PCA) was used to analyze inter-group differences and screen differential metabolites. Significantly differential metabolites were further analyzed for pathway enrichment using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. One major differential metabolite was selected for in vitro experiments to verify its effect on osteogenic differentiation of mouse embryonic preosteoblasts MC3T3-E1. Results ·Probing depth (PD), clinical attachment loss (CAL), and plaque index (PI) in the CRF group were significantly higher than those in the CP group (all P<0.05). In the CRF group, urea level (r=0.41) and creatinine level (r=0.61) were positively correlated with PD, and creatinine level was also positively correlated with CAL (r=0.53). Estimated glomerular filtration rate (eGFR) was negatively correlated with PD (r=-0.69) and CAL (r=-0.56), respectively. PCA results showed significant differences in metabolite profiles among the three groups, with phosphoric acid presenting remarkable differences. KEGG analysis revealed that the enriched differential metabolites were mainly involved in protein digestion and absorption, neuroactive ligand-receptor interaction, sphingolipid metabolism, necroptosis, choline metabolism in cancer, ovarian steroidogenesis, sphingolipid signaling, and mineral absorption. In vitro experiments confirmed that 4 mmol/L phosphate ions downregulated the mRNA and protein expression levels of Runt-related transcription factor 2 (Runx2), alkaline phosphatase (Alp), and osteocalcin (Ocn) in MC3T3-E1 cells (all P<0.05), thereby inhibiting osteogenic differentiation. Conclusion ·Periodontal tissue destruction is more severe in periodontitis patients complicated with CRF than those without CRF. Upregulated salivary phosphorus concentration may be one of the mechanisms by which chronic kidney disease aggravates periodontal tissue destruction. Excessively high phosphorus concentration can inhibit osteogenic differentiation.