Oral squamous cell carcinoma (OSCC) is a growing global public health problem that seriously affects the quality of life of humans (Panarese et al. 2019), and due to its malignant nature, it accounts for the highest morbidity and mortality among head and neck cancers (Ni et al. 2014). Despite rapid advances in diagnosis and treatment in recent years, the overall survival rate of OSCC remains low due to local or distant metastasis and recurrence (Almangush et al., 2020, Ling et al., 2021). The typical therapeutic strategies include post-surgery radiation and chemotherapy surgery, but drug resistance remains a significant challenge (Law et al. 2021). Therefore, developing new drugs is imperative to improve the treatment effect for OSCC.

Chinese medicine has been previously reported as a supplement for cancer treatment, including OSCC (Wang et al. 2020). Verbascoside, also called acteoside, is an active phenylethanoid glycoside originally isolated from mullein and can also be isolated from lilac and greater broomrape (Alipieva et al. 2014). It has been reported to possess multiple biological activities, including antioxidant, anti-inflammatory, anti-tumor, wound healing, and neuroprotective (Attia et al., 2018, Wu et al., 2021). Similarly, it has also been demonstrated to inhibit the proliferation and metastasis of tumor cells and induce cell apoptosis (Jia et al., 2018, Daneshforouz et al., 2021). It has also been reported to inhibit the proliferation and metastasis of OSCC cells and promote apoptosis without significant in vivo adverse effects (Zhang et al. 2018a). However, the underlying molecular mechanism of verbascoside remains unclear.

N6-Methyladenosine (m6A) methylation is a common RNA modification, including in mRNA and non-coding RNA (Huang et al. 2020), a reversible modification process that can be methylated by methyltransferases (writers) and demethylated by demethylases (erasers), and m6A binding proteins (readers) are used for m6A recognition. Similarly, methyltransferase-3 (METTL3) is key in regulating methyltransferase complex and cancer development (Zeng et al. 2020). METTL3 has been reported to act as an oncogene in OSCC. METTL3 knockdown inhibited OSCC cell proliferation, self-renewal, migration, and invasion, and the apposite results were showed after METTL3 overexpression (Liu et al., 2020, Xu et al., 2021). Additionally, microRNAs (miRNAs) are associated with tumor type, stage, development, and prognosis (Lee & Dutta (2009)). The m6A on pri-miRNAs could be recognized by hnRNPA2B1, which interacts with DGCR8, promoting miRNA processing and inducing their maturation (Alarcón et al. 2015a). Thus, it is imperative to investigate the role of METTL3-regulated miRNAs in OSCC.

This project aimed to investigate the role of verbascoside in OSCC and the underlying molecular mechanisms, which are envisaged to provide new therapeutic directions in treating OSCC.