Targeting circFOXO3 to Modulate Integrin β6 Expression in Periodontitis: A Potential Therapeutic Approach

ABSTRACT Aims Circular RNA forkhead box O3 (circFOXO3) is crucial in regulating inflammation in lung and heart injuries. However, its role in periodontitis remains unclear. We sought to elucidate the effects of circFOXO3 on periodontitis progression and related molecular mechanisms. Methods Reverse‐transcription quantitative polymerase chain reaction and fluorescence in situ hybridization were used to quantify and localize circFOXO3 expression. The mechanism by which circFOXO3 promotes inflammation in periodontitis was investigated using epithelial cells, human gingival epithelium and a rat model of ligature‐induced periodontitis. Results circFOXO3 expression was abnormally high in the gingival epithelial tissues of patients with periodontitis. Elevated circFOXO3 levels down‐regulated microRNA (miR)‐141‐3p, leading to increased FOXO3 expression. FOXO3 interacted with JunB to form a transcriptional‐repression complex that inhibited the integrin β6 (ITGβ6)‐mediated activation of transforming growth factor β (TGF‐β) in epithelial cells. Through the miR‐141‐3p/FOXO3/JunB axis, circFOXO3 suppressed TGF‐β signalling, thereby exacerbating periodontal inflammation. Finally, circFOXO3 inhibition hindered disease progression and restored TGF‐β activity in vivo via the FOXO3/JunB/ITGβ6 pathway. Conclusion Our study identified a novel mechanism by which circFOXO3 contributes to periodontal inflammation through a complex transcriptional regulatory network involving miR‐141‐3p, FOXO3, JunB and ITGβ6. These findings highlight potential therapeutic targets for the development of effective treatments for this debilitating disease.