CALR-Regulated Lactylation Modifications in Periodontitis: Insights from Bulk and Single-Cell RNA Sequencing

Background Lactic acid accumulates in periodontal tissues during periodontitis, suggesting disrupted metabolism may contribute to disease progression. However, the role of lactic acid and its modifications, such as lactylation, remains unclear. Methods Gingival tissues were collected from healthy controls and periodontitis patients. Protein lactylation levels were evaluated through immunohistochemistry and molecular detection. A mouse periodontitis model was established with local lactate intervention, and bone resorption was quantified using micro-computed tomography (micro-CT). Periodontitis transcriptomic and single-cell sequencing data from the Gene Expression Omnibus (GEO) database were integrated to screen differentially expressed lactylation-related genes (DE-LRGs). The Least Absolute Shrinkage and Selection Operator (LASSO), random forest, and support vector machine (SVM) algorithms were applied to identify core genes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) was employed to analyze their association with immune infiltration. A CALR knockdown mouse model was constructed to validate gene function. Results Protein lactylation levels were significantly elevated in gingival tissues of periodontitis patients and positively correlated with inflammation severity. In mouse models, lactate intervention alleviated gingival inflammation and bone resorption. Through multi-omics analysis, CALR was identified as a core regulatory factor among key lactylation-related genes. CALR knockdown mice exhibited decreased lactate levels, aggravated inflammation, and significantly increased bone resorption, confirming its role in regulating the periodontal immune microenvironment through lactate metabolism. Conclusions Lactylation modification participates in immune regulation during periodontitis. The screened core LRGs, especially CALR , represent potential therapeutic targets.