Silencing PAR-2 in macrophages promotes PANoptosis and triggers duodenal microinflammation in functional dyspepsia.

Macrophage PANoptosis may play a critical role in the development of functional dyspepsia (FD). It not only affects the balance and regulation of the immune system but also participates in the pathogenesis of FD, possibly by affecting the motor and sensory functions of the gastrointestinal tract. In this study, key genes related to PANoptosis and macrophages were identified using weighted gene co-expression network analysis (WGCNA) and Mendelian randomization. Their function was further explored through gene set enrichment analysis (GSEA). In vivo and in vitro experiments were conducted to examine the role of macrophages in FD duodenal micro-inflammation and the involvement of key genes in macrophage PANoptosis. A total of 489 target genes were identified by intersecting 1537 differentially expressed genes with 10,436 PANoptosis-related module genes. Among them, ARL5B, CAPN3, CDK5RAP3, and F2RL1 showed a causal relationship with FD. Functional enrichment results revealed that these key genes, particularly PAR-2, are involved in NF-κB, AMPK, Toll-like receptors, and other signaling pathways. Moreover, this study showed that silencing PAR-2 in macrophages promoted PANoptosis and triggered duodenal micro-inflammation in FD. These findings suggest that the NF-κB-PAR-2 axis may serve as a central regulatory mechanism that plays an important role. This study offers novel insights and potential targets for the clinical diagnosis and treatment of FD.