Cervical Cancer (CC) is a significant health concern, and over 99.7 % of CC cases are attributed to high-risk papillomavirus (hr-HPV) infection [1,2]. The global pursuit of CC elimination by approaches encompassing prevention, screening and treatment is encountering challenges such as the epidemiological disparity of CC prevalence tied to regional socioeconomic situations and the lack of effective therapeutic options for advanced CC [3,4].

.The progressive global DNA hypomethylation coupled with local hypermethylation of the promoter of tumour suppressor genes leads to chromosomal instability and gene silencing, driving the transition from pre-cancerous lesions to invasive cancer [5]. DNA methylation at the fifth position of cytosine (5mC) is one of the most important epigenetic modifications for gene expression and cell differentiation to maintain the pluripotent state of stem cells and control embryo development, genomic imprinting, and immune cell differentiation. The formation of 5mC at the promoter region interferes with transcriptional regulation and indirectly affects the chromatin organization [6]. TET1 is one of the Ten-eleven translocation (TET) 5-methylcytosine dioxygenase family members that actively hydroxylate and erase the methyl group from 5mC, thereby demethylating the 5’-CpG-3′ dinucleotides into the reduced form 5-hydroxymethylcytosine (5hmC), 5-formaylcytosine (5fmC) or 5-carboxylcytocine (5cmC) [7].

TET1 is generally considered a tumour suppressor in some solid tumours [7]. However, its expression is reported to be over- or under-regulated in different or even the same cancer [7]. Reverse relationships between TET1 and some cancer propellants have been revealed in cervical cancer. TET1 deficiency or mutation was associated with Wnt/β-catenin overactivity, metastasis and poor prognosis of solid tumours in organs such as colon [8], ovary [9], pancreas [10], Gastric [11], and lung [12]. However, little is known about its involvement in the Wnt/β-catenin signalling in cervical cancer. The evolutionarily conserved Wnt/β-catenin signalling is the most altered pathway in cervical cancer, constituting one of the “second hits” required for the viral survival in the host and cancer initiation, according to a genome-wide survey comparing the normal and cancer cervix epithelial [13,14]. The conventional therapeutic modalities are preferably complemented by diet-derived compounds such as resveratrol (3,5,4′-trihydroxy-trans-stilbene, RES), thanks to its low toxicity and multifaceted biological benefits [15]. RES is a natural polyphenol found in plants such as the skin of red grapes, peanuts and berries, as part of the natural protective response to pathogenic damage. The health benefits of RES extend to almost all medical disciplines across cardiovascular diseases, neurodegeneration, metabolic disorders, and cancer [16]. RES antagonises cervical cancer cell survival and progression, promotes apoptosis and cell cycle arrest, inhibits clonogenesis and invasion, and sensitises radio responses [17,18], through modulation of pathways such as the hedgehog signalling [19] and E6/E7/p53 activity [20,21]. By promoter demethylation and histone modification in some cancers, RES treatment epigenetically re-activates tumour suppressor genes, such as BRAC1 and p53 in breast cancer [22], Run-related transcription factor 3 (RUNX3) in melanoma [23], and CRABP2 in thyroid cancer [24], thereby limiting cell proliferation, migration, and invasion. In prostate cancer cells, genomic DNA methylation can be re-modelled by RES via upregulating TET1 levels [25]. The present study aimed to explore whether TET1-related epigenetic modulation takes part in the regulation of RES on Wnt/β-catenin activity in cervical cancer and how it influences cancer development.