Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival biofilm. The therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative stress. Sinensetin (Sin) is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant activities. Our study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular mechanisms. We found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells (PDLCs) under inflammatory conditions. Administered Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in vivo. By molecular docking, we identified Bach1 as a strong binding target of Sin, and this binding was further verified by cellular thermal displacement assay and immunofluorescence assays. Chromatin immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter, subsequently upregulating the expression of the key antioxidant factor HO-1. Further functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant effects. Additionally, we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1, thereby inducing HO-1 expression and inhibiting oxidative stress. Overall, Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.

牙周炎是由龈下生物膜引起的慢性炎症和免疫反应性疾病。对于易感患者来说，由于过度的炎症反应和氧化应激，治疗效果往往不理想。 Sinensetin (Sin) 是一种天然的多甲氧基黄酮类化合物，具有抗炎和抗氧化活性。我们的研究旨在探讨Sin对牙周炎的有益作用及其具体分子机制。我们发现 Sin 可以减轻炎症条件下牙周膜细胞 (PDLC) 的氧化应激和炎症水平。对结扎诱导牙周炎模型的大鼠施用 Sin，在体内表现出对牙周炎的保护作用。通过分子对接，我们确定Bach1是Sin的强结合靶点，并通过细胞热位移测定和免疫荧光测定进一步验证了这种结合。染色质免疫沉淀-定量聚合酶链反应结果还表明，Sin 阻碍 Bach1 与 HMOX1 启动子的结合，随后上调关键抗氧化因子 HO-1 的表达。对 Bach1 敲除和过度表达的进一步功能实验证实 Bach1 是 Sin 发挥其抗氧化作用的关键靶点。此外，我们证明 Sin 通过增强 Bach1 的泛素化降解来促进 Bach1 的减少，从而诱导 HO-1 表达并抑制氧化应激。总体而言，Sin 通过靶向与 Bach1 结合，可能成为治疗牙周炎的有前途的候选药物。