Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system

  • Int J Oral Sci. 2022 May 31;14(1):27. doi: 10.1038/s41368-022-00177-1.
Liangjing Xin   #  1 ,  Fuyuan Zhou   #  1 ,  Chuangwei Zhang  1 ,  Wenjie Zhong  1 ,  Shihan Xu  1 ,  Xuan Jing  1 ,  Dong Wang  2 ,  Si Wang  1 ,  Tao Chen  3 ,  Jinlin Song  4
Affiliations
  • 1. College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China.
  • 2. Department of Ultrasound, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 3. College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China. [email protected].
  • 4. College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 35637195 DOI: 10.1038/s41368-022-00177-1
Abstract

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.

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