Ruscogenin Targets TXNIP to Suppress PANoptosis and Inflammation in Periodontitis

ABSTRACT Objective This study explored the role of PANoptosis, a coordinated form of regulated cell death, in periodontitis (PD), aiming to identify key PANoptosis‐related genes and evaluate potential small‐molecule inhibitors. Methods PANoptosis activity in periodontal tissues was assessed using ssGSEA. Differentially expressed PANoptosis‐related genes were identified from GEO datasets (GSE10334, GSE16134). GO/KEGG enrichment, WGCNA, and multiple machine‐learning methods were used to screen hub genes, followed by ROC validation and confirmation in clinical samples. Molecular docking and molecular dynamics simulations were performed to identify compounds targeting TXNIP. Single‐cell RNA‐seq was used to localize gene expression in immune subsets. Cell experiments examined TXNIP‐mediated PANoptosis signaling, and a mouse PD model was used to verify inflammatory responses and tissue destruction in vivo. Results TXNIP was identified as a key PANoptosis‐associated gene broadly expressed in gingival cells and linked to PANoptosis activation. Ruscogenin was predicted and validated to suppress TXNIP‐related PANoptosis and periodontal inflammation. Conclusions TXNIP acts as an important PANoptosis‐associated regulator in PD, while ruscogenin shows therapeutic promise by inhibiting TXNIP‐related inflammatory cell death, providing new insight into PANoptosis mechanisms in PD progression.