Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate (4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time, the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2^−/− mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment. Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction, ameliorate local inflammation for more predictable periodontitis.

牙周炎是一种广泛存在的口腔疾病，其特征是牙周组织的持续炎症和不可逆的牙槽骨丢失，最终导致牙齿脱落。衣康酸四辛酯 (4-OI) 是一种可渗透细胞的衣康酸酯衍生物，已被公认为治疗炎症性疾病的有希望的治疗靶点。在这里，我们首次探讨了 4-OI 对抑制牙周破坏、改善局部炎症的保护作用以及牙周炎的潜在机制。在这里，我们发现 4-OI 治疗可改善牙周微环境中脂多糖诱导的炎症。正如在 C57BL/6 小鼠实验性牙周炎样本中观察到的，4-OI 还可以通过 Nrf2 激活显着减轻炎症和牙槽骨丢失。这进一步证实了沉默 Nrf2 通过下调下游抗氧化酶的表达来阻断 4-OI 的抗氧化作用。此外，分子对接模拟表明了 Nrf2 激活下的可能机制。此外，在 Nrf2^-/-小鼠，4-OI 治疗不能防止因诱导牙周炎引起的牙槽骨功能障碍，这强调了 Nrf2 在 4-OI 介导的牙周炎治疗中的重要性。我们的结果表明，4-OI 通过 KEAP1-Nrf2 的解离和 Nrf2 信号级联的激活来减轻炎症和氧化应激。总之，4-OI 的局部给药提供了抑制牙周破坏、改善局部炎症以实现更可预测的牙周炎的临床潜力。