Periodontitis is a common inflammatory oral disease, which is caused by pathogenic microflora in the subgingival microbiome and biofilms or dental plaque that forms adjacent to teeth on a daily basis (Darveau, 2010; Schieffer et al., 2022). When suffering from periodontitis, there are not only a mass of inflammatory cytokines, including Interleukin-1β, Interleukin-6, and tumor necrosis factor-α in periodontal tissues (Kim et al., 2020; Shao et al., 2009), but also the imbalance of oxidative stress (Chen et al., 2019). While periodontitis develops to the later stage, it can result in extensive alveolar bone defects, and eventual teeth loss (Helal et al., 2019), exerting a great negative impact on life. In addition to teeth loss, a mass of literature have confirmed that periodontitis is associated with various critical systemic illnesses, such as cardiovascular diseases (Petrenya et al., 2022), respiratory diseases (Tamimi et al., 2022), nervous system diseases (Wang et al., 2019), and even cancer (Niture et al., 2014). Hence, there is a wide range of social needs to prevent the process of periodontitis.

Nuclear factor erythroid-2 related factor 2 (Nrf2), a member of the CNC-bZIP protein family (Schieffer et al., 2022), has been widely described as the activator of cellular defense mechanism (Houghton et al., 2016) and plays a significant role of cellular defense in antioxidant, anti-inflammatory and immune response (Chiu et al., 2017a). On the one hand, it can up-regulate the expression of detoxification genes and antioxidants, on the other hand, Nrf2 can also inhibit the expression of proinflammatory factors such as cytokines, inflammatory chemokines and cell adhesion factors (Chiu et al., 2017b; Liu et al., 2017). Besides, Nrf2-related signaling pathways are involved in pathological bone diseases such as osteoporosis, osteoarthritis and periodontitis by participating in the regulation of bone mass and bone mineral density, and are closely related to the proliferation and differentiation of osteoclasts and osteoblasts (Wu et al., 2022). Nrf2 has been shown to take part in other cellular processes, like regulating mitochondrial bioenergetics, autophagy, intermediate metabolism, stem cell quiescence and unfolded protein response (Tonelli et al., 2018).

We have noticed that long-term exposure to inflammation and oxidative stress is considered to be the causes of inducing and aggravating periodontitis (Araújo et al., 2017). In the meantime, a mounting number of studies indicated that many phytochemicals such as Quercetin and Biochanin A have the ability to activate Nrf2 (Liang et al., 2019; Zhou et al., 2019). Nrf2 related pathways could be regulated by these Nrf2-activators to inhibit the body's inflammatory response and oxidative stress response, so as to reduce alveolar bone resorption and effectively alleviate the symptoms of periodontal disease (Ying et al., 2020; Zhang et al., 2020; Zhao et al., 2021). It can be preliminarily assumed that Nrf2 has certain functional implications for periodontitis, suggesting Nrf2 to be a potential therapeutic inhibitor of periodontitis. To sum up, the effect of Nrf2 on periodontitis is a problem worthy of attention.

From what has been mentioned above, although a great number of in vitro experiments have shown that Nrf2 has a certain correlation with periodontitis in terms of antioxidant stress, anti-inflammatory and bone homeostasis maintenance (Huang et al., 2020; Huang et al., 2022; Liu et al., 2017; Xiong et al., 2020), the counts of researches on the preclinical animal are still small. There is no denying that many differences existed between preclinical and clinical studies due to the complexity of clinical conditions. However, the systematic review of preclinical animal data can partially explain the potential mechanism of clinical diseases and point out the direction of clinical treatment (Bertl et al., 2018). Therefore, we have evaluated the changes of Nrf2 levels in animal periodontitis models and analyzed the clinical benefits of Nrf2 activation in the same models to investigate the functional implications of Nrf2 in periodontitis. Understanding the character of Nrf2 in animal periodontitis models is necessary for its use as a potential therapeutic target either for the treatment or prevention of periodontitis in the future.