Kcnn4-Mediated K+ Efflux Activates Nlrp3 In Orthodontic Bone Remodeling

The inflammatory microenvironment plays a critical role in orthodontic alveolar bone remodeling. Potassium ion (K+) efflux is a key signaling event in inflammation, yet its role in this process remains unclear. This study aims to identify key potassium ion channel involved in orthodontic alveolar bone remodeling and elucidate its role in mediating inflammation. RNA-seq data (GSE109167) was analyzed using KEGG and GO enrichment to identify KCNN4 as a mechanically responsive potassium channel. With ethical approval, periodontal ligament cells (PDLCs) were isolated from extracted premolars of 12–18-year-old orthodontic patients. Mechanical stress (1.5 g/cm²) was applied in vitro, and K+ efflux was assessed by intracellular K+ concentration and KCNN4 expression were assessed via qPCR. KCNN4 inhibition with Senicapoc was followed by western blot, immunofluorescence, and ELISA to evaluate NLRP3 activation and inflammatory cytokine expression. Bioinformatics and transcriptomic analysis identified FoxO1 as a potential NLRP3 transcription factor, validated by ChIP-qPCR and dual-luciferase assays. Functional studies used si-FoxO1 knockdown. An OTM model was established in 6–8-week-old male SD rats, with Senicapoc administration. Micro-CT and histology assessed tooth movement, alveolar bone remodeling, and inflammation. Senicapoc inhibited NLRP3 activation in PDLCs under mechanical stress. FoxO1 was identified as an NLRP3 transcription factor, and siFoxO1 knockdown reduced its activation. In vivo, Senicapoc suppressed periodontal inflammation and inhibited OTM. Mechanical stress activates KCNN4-mediated K+ efflux in PDLCs, promoting FoxO1 nuclear translocation and NLRP3 transcription, thereby mediating inflammation in orthodontic bone remodeling.