The human oral cavity, which is colonized by over 700 types of microorganisms, resembles a cornucopia of bacteria (Peng et al., 2022). The oral microbiome, one of the five research priorities (oral cavity, nasal cavity, vagina, intestine, and skin) of the human microbiome project (HMP), exhibits the second highest level of alpha diversity (diversity within individuals) after the gut microbiome (Stasiewicz & Karpiński, 2022). With the progression of the HMP, our understanding of oral microbes has significantly evolved, expanding beyond their association with oral diseases, such as caries and periodontal diseases. Often considered part of the normal oral microbiome, Fusobacterium nucleatum is an opportunistic commensal gram-negative anaerobic bacterium implicated in various forms of periodontal disease (Brennan & Garrett, 2019). However, F. nucleatum may also be associated with several systemic disorders and diseases such as atherosclerosis, inflammatory bowel diseases, and adverse pregnancy outcomes including preterm labor, stillbirth, and chorioamnionitis (Brennan & Garrett, 2019). Moreover, F. nucleatum is involved in breast (Parhi et al., 2020) and colorectal (Ma et al., 2018) carcinogenesis and is often associated with advanced tumor stage and poor prognosis. Notably, F. nucleatum has been associated with oral, head and neck, esophageal, cervical, and gastric cancers (Brennan & Garrett, 2019).

Epithelial-mesenchymal transition (EMT) is a multifaceted and often reversible process in which epithelial cells gain increased migratory and invasive capacities by transforming into mesenchymal cells (Yang et al., 2020). This process is commonly associated with various physiological and pathological conditions, including embryonic development, tissue repair, cancer metastasis, and chronic fibrosis (Kim et al., 2017). Notably, the process of EMT in cancer cells does not depend on accumulating mutations but is rather epigenetically orchestrated by signals from the microenvironment (Brabletz et al., 2021). Increasing evidence suggests that bacteria are involved in EMT in many types of cancers, such as Helicobacter pylori in gastric cancer (Jamal Eddin et al., 2023), Porphyromonas gingivalis in esophageal cancer (Chen et al., 2021), and F. nucleatum in colorectal cancer (Ma et al., 2018). Notably, F. nucleatum is reportedly enriched in oral squamous cell carcinoma (OSCC) tissues compared to adjacent normal tissues, sparking interest in the relationship between F. nucleatum and OSCC (Irfan et al., 2020). Recently, F. nucleatum was shown to be associated with EMT in OSCC (McIlvanna et al., 2021, Zhang et al., 2020).

Many natural plant compounds exhibit potent biological effects and have been used for many years as a source of therapeutic substances and as a structural basis for drug development (Avila-Carrasco et al., 2019). For example, berberine has been used for the treatment of type II diabetes (Yin et al., 2008) and celastrol has been used in combination with nifedipine in clinical trials to investigate preeclampsia treatment outcomes (Xiao et al., 2017). Among these compounds, resveratrol (trans-3,5,4’-Trihydroxystilbene) has attracted considerable research attention owing to its antioxidant properties. Resveratrol is a natural phytoalexin produced by plants as a defense mechanism against environmental stress and pathogen invasion (Ren et al., 2021). Resveratrol has been widely utilized for its pharmacological effects and safety as a dietary supplement, food additive, and natural health food (Sun et al., 2019). Resveratrol exhibits anti-inflammatory properties, reverses doxorubicin resistance, and inhibits EMT in many types of cancer cells (Avila-Carrasco et al., 2019, Buhrmann et al., 2019, Malaguarnera, 2019, Xu et al., 2017). Nevertheless, its effect on EMT associated with F. nucleatum in OSCC remains poorly understood.

In the present study, we aimed to investigate the effects of resveratrol on F. nucleatum-induced EMT in OSCC. We first established an in vitro model of F. nucleatum-induced EMT in OSCC cells. We used transforming growth factor beta 1 (TGF-β1) as a positive control for the EMT model, given its role as an important driver of EMT in various cancers, including OSCC (Lv et al., 2021). We then explored the appropriate concentration of resveratrol and its effects on F. nucleatum-induced EMT in OSCC, which may provide a target for OSCC treatment.