Xu Mingyan, Zhu Feixiang, Guo Yifan, Liu Fan, Shi Songlin, Yang Ling, Huang Rui, Deng Xiaoling
Department of Implantology, Stomatological Hospital of Xiamen Medical College & Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment, Xiamen, China.
Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, China.
J Clin Periodontol. 2025 Apr;52(4):651-664. doi: 10.1111/jcpe.14124. Epub 2025 Jan 12.
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.
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.
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.
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.
环状RNA叉头框O3（circFOXO3）在调节肺部和心脏损伤中的炎症反应方面至关重要。然而，其在牙周炎中的作用尚不清楚。我们试图阐明circFOXO3对牙周炎进展的影响及其相关分子机制。
采用逆转录定量聚合酶链反应和荧光原位杂交技术对circFOXO3的表达进行定量和定位。利用上皮细胞、人牙龈上皮细胞和结扎诱导的牙周炎大鼠模型，研究circFOXO3促进牙周炎炎症反应的机制。
circFOXO3在牙周炎患者的牙龈上皮组织中表达异常增高。circFOXO3水平升高下调了微小RNA（miR）-141-3p，导致FOXO3表达增加。FOXO3与JunB相互作用形成转录抑制复合物，抑制上皮细胞中整合素β6（ITGβ6）介导的转化生长因子β（TGF-β）的激活。通过miR-141-3p/FOXO3/JunB轴，circFOXO3抑制TGF-β信号传导，从而加剧牙周炎症。最后，circFOXO3抑制在体内通过FOXO3/JunB/ITGβ6途径阻碍疾病进展并恢复TGF-β活性。
我们的研究发现了一种新机制，即circFOXO3通过涉及miR-141-3p、FOXO3、JunB和ITGβ6的复杂转录调控网络促进牙周炎症。这些发现突出了针对这种使人衰弱的疾病开发有效治疗方法的潜在治疗靶点。
