OBJECTIVE: This study aimed to identify crosstalk genes shared between periodontitis (PD) and atherosclerosis (AS) and to investigate their potential connections with pyroptosis-related genes. The goal was to uncover common regulatory mechanisms underlying these two inflammatory conditions. METHODS: Gene expression datasets for PD (GSE10334) and AS (GSE43292) were retrieved from public databases. Following batch effect correction and normalization, differential expression analysis was conducted using the limma package in R. Functional enrichment analysis was performed with the clusterProfiler package to identify key pathways, while heatmaps and pathway networks were constructed to visualize the relationships among pyroptosis genes and crosstalk genes. Weighted gene co-expression network analysis (WGCNA) was applied to identify critical modules, and the diagnostic potential of core genes was evaluated via receiver operating characteristic (ROC) analysis. Protein-protein interaction (PPI) networks were also constructed to explore molecular interactions. RESULTS: A total of 28 downregulated and 105 upregulated genes were identified in the PD dataset, while the AS dataset revealed 55 downregulated and 56 upregulated genes. Thirteen crosstalk genes were identified between the two datasets. Enrichment analyses of these crosstalk genes highlighted their involvement in inflammation- and immune-related pathways. The observed association of pyrototic phenotypes with PD and AS indicated significant overexpression of pyroptosis-related genes such as CASP1, NLRP3, and GSDMD, suggesting the participation of pyroptosis in the progression of disease. The WGCNA suggested that pyroptosis genes are closely relevant to immune responses and cell death processes. Data up to October 2023 were used to perform receiver operating characteristics (ROC) curves to confirm the diagnostic value of the enriched core genes, and all of them presented AUC values >
0.8, which meant that they were key genes with effective diagnostic power. CONCLUSION: We report a novel study that identifies differentially expressed genes and pyroptosis-related pathways in PD and AS with shared inflammatory mechanisms. These results underscore the crucial role of pyroptosis in disease progression, suggesting its potential as a focus of diagnostic and therapeutic strategies. These findings provide insights for dissecting the molecular basis of inflammatory diseases.