Prediction of the SREBP1-ISYNA1-inositol axis in butyrate-induced pyroptosis and lipid metabolic dysregulation in periodontitis.

BACKGROUND/PURPOSE: Periodontitis is a prevalent inflammatory disease influenced by host-microbe interactions. Butyrate, a bacterial metabolite, has been implicated in disease progression, though its precise mechanism remains unclear. This study aims to elucidate how butyrate promotes gingival epithelial pyroptosis and disrupts metabolic homeostasis, contributing to periodontal pathology. MATERIALS AND METHODS: Human gingival tissues from periodontitis patients and healthy controls were analyzed. In vitro models using gingival epithelial cells were treated with butyrate to assess pyroptosis via N-terminal domain of gasdermin E (GSDME-N) expression. Lipid metabolism alterations were evaluated through transcriptomic profiling and lipid droplet accumulation. Molecular mechanisms were explored by examining sterol regulatory element-binding protein 1 (SREBP1) activation, inositol-3-phosphate synthase 1 (ISYNA1) promoter binding, and interactions between GSDME-N and phosphoinositides/cardiolipin. Clinical validation was performed via immunohistochemistry. RESULTS: GSDME-N was significantly upregulated in periodontitis gingival tissues and associated with epithelial barrier disruption. Butyrate triggered GSDME-dependent pyroptosis, resulting in lipid droplet accumulation and widespread dysregulation of lipid metabolism. Butyrate activated the transcription factor SREBP1, which bound to the ISYNA1 promoter and enhanced inositol and phosphoinositide metabolism. Furthermore, GSDME-N directly interacted with phosphoinositides and cardiolipin, connecting inositol signaling to pyroptosis execution. Clinical samples consistently showed elevated levels of nuclear SREBP1 and ISYNA1 in periodontitis. CONCLUSION: These findings reveal the SREBP1-ISYNA1-Inositol axis as a probable pathway through which butyrate induces gingival epithelial pyroptosis and metabolic dysfunction, providing new mechanistic insights and potential therapeutic targets for periodontitis.