Exploring the interconnection between PANoptosis and chronic inflammatory diseases: identifying key targets and therapeutic strategies for periodontitis and ulcerative colitis.

Abstract

Periodontitis (PD) and ulcerative colitis (UC) are chronic inflammatory diseases that may share underlying molecular mechanisms, potentially mediated by PANoptosis, which integrates pyroptosis, apoptosis, and necroptosis. Understanding their interaction could unveil novel therapeutic targets. This study aimed to identify key targets and pathways linked to PD and UC, explore the interaction between PANoptosis-related genes and PD-UC-related genes, and predict potential therapeutic targets and drugs for PD-UC. In this study, we acquired datasets from the GEO database, including GSE16134 for PD and GSE87466 for UC. Disease-related targets were identified through differential expression analysis and weighted gene co-expression network analysis. These targets were compared with PANoptosis-related targets and used to form protein-protein interaction networks. Enrichment analyses, such as GO and KEGG, were conducted to investigate the biological significance. Core genes were pinpointed utilizing LASSO and SVM-RFE algorithms, and their expressions were verified in an experimental PD and DSS-induced UC mouse model and single-cell RNA sequencing. A ceRNA network was established, and potential drugs targeting core genes were predicted. Molecular docking simulations were performed to determine binding interactions. As a result, a total of 107 intersected genes were identified, with BAG3, LYN, and APOE recognized as core targets. These genes were significantly associated with immunological processes and inflammatory pathways, as evidenced by enrichment analyses. Histological and molecular validation in mice confirmed their differential expression in PD and UC. Single-cell RNA sequencing revealed cell-type-specific expression of core genes, with Lyn enriched in myeloid cells and Apoe in fibroblasts. A ceRNA network highlighted regulatory interactions, while drug prediction pinpointed potential therapeutic agents for LYN and APOE. In conclusion, the study identifies core genes and their molecular networks bridging PANoptosis with PD and UC, underscoring the potential of BAG3, LYN, and APOE as therapeutic targets. These discoveries establish PANoptosis as a novel therapeutic axis for chronic inflammatory comorbidities, bridging the gap between oral and intestinal mucosal immunity.