Periodontitis, commonly known as periodontal disease or gingival disease, is a chronic inflammatory condition that affects the supporting structures of the teeth, including the gingival, periodontal ligament, cementum, and alveolar bone (Heitz-Mayfield, 2024). It is initiated by the accumulation of bacterial plaque on the tooth surface, which, if left untreated, can lead to a progressive destruction of the periodontal ligament and alveolar bone, ultimately resulting in tooth loss (Könönen et al., 2019, Lin et al., 2021). The disease is characterized by symptoms such as gingival inflammation, bleeding, redness, swelling, and eventually, the formation of periodontal pockets. These pockets provide an environment for further bacterial colonization and infection, perpetuating the cycle of inflammation and tissue destruction (Salvi et al., 2023). A large number of studies in recent years have gradually emphasized the importance of cellular pyroptosis in the development and progression of periodontitis caused by dental plaque microorganisms (Li et al., 2021, Xiang et al., 2024, Yang et al., 2024). In the context of periodontitis, the activation of pyroptosis can be triggered by various factors, including the presence of bacterial lipopolysaccharides (LPS) and other noxious stimuli associated with the periodontal pathogen biofilm (Chen et al., 2021).Therefore, an in-depth study of the relationship between pyroptosis and periodontitis and exploration of prevention and and treatment of periodontitis are of great significance for oral health and general health.

Cell pyroptosis was a highly regulated form of programmed cell death. During pyroptosis, the inflammatory vesicle nucleotide-binding domain and leucine-rich repeat-containing family of pyrin domain-containing 3 (NLRP3) is activated, followed by recruitment and activation of caspase-1. caspase-1 shears pro-interleukin-18 (pro-IL-18), pro-interleukin-1β (pro-IL-1β) into active forms of IL-18 and IL-1β and releases them extracellularly through Gasdermin D (GSDMD)-mediated membrane pores (Liu et al., 2016). Pyroptosis amplifies local and systemic inflammatory responses by releasing IL-18 and IL-1β. Previous studies have revealed that upregulation of NLRP3 inflammatory vesicles in gingival tissues of patients with periodontitis promotes periodontal tissue destruction (Aral et al., 2020, Olsen and Yilmaz, 2016). The NLRP3 inflammasome has been implicated in the initiation of pyroptosis in response to these periodontal pathogens (Huang et al., 2020). In an experimental rat model of periodontitis, inhibition of the onset of cellular pyroptosis attenuated inflammation in periodontal tissues and was able to reduce alveolar bone resorption (Zhang et al., 2022). Therefore, understanding the interaction mechanism between pyroptosis and periodontitis is crucial for the development of novel therapeutic strategies.

Stimulator of interferon genes (STING) is an essential adaptor protein that plays a pivotal role in the innate immune response. It is a key component of the cytosolic DNA sensing pathway, which is crucial for detecting invading pathogens and initiating a cascade of antiviral responses (Dansako et al., 2016, Paul et al., 2021). In addition to its role in antiviral immunity, STING has been implicated in the regulation of various cellular processes, including the modulation of inflammation, cell death pathways, and the promotion of tissue repair (Chen & Xu, 2023). However, dysregulation of STING signaling has also been associated with a range of diseases, including autoimmune disorders and inflammatory diseases (Decout et al., 2021, Zhang et al., 2020). Recent studies have revealed that LPS stimulation contributes to STING activation, which triggers cellular pyroptosis, and that targeting the STING-NLRP3 axis attenuates the inflammatory response during bacterial and viral infections (Cao et al., 2024, Gaidt et al., 2017, Luo et al., 2024, Ning et al., 2020). A recent study revealed that STING was strongly positively expressed in the connective tissue of patients with periodontitis (Elmanfi et al., 2021). However, the exact function and mechanism of action of STING in periodontitis have not yet been elucidated.

In this study, we aimed to investigate the effects of STING on pyroptosis and inflammation in LPS-induced HGFs. In addition, we further evaluated whether STING regulates cellular pyroptosis and inflammation by activating the NF-κB/NLRP3 pathway. Our findings may provide a theoretical basis for future targeted inhibition of STING for the treatment of periodontitis.