Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck globally, characterized by high metastatic potential, high recurrence rates, and poor prognosis, posing serious health and life threats to patients [2]. Despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, the prognosis for OSCC patients remains unsatisfactory, particularly for those with advanced or recurrent disease, where treatment efficacy is notably limited [13]. Cisplatin (DDP), as a first-line chemotherapeutic agent, is used in the treatment of various cancers, including OSCC; however, the issue of drug resistance presents a significant challenge in clinical management [4], [6], [16], [20]. Therefore, exploring the molecular mechanisms underlying DDP sensitivity in OSCC cells and identifying new therapeutic targets is of great importance for improving patient prognosis.

Ferroptosis is a recently discovered form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides [25]. In recent years, the role of ferroptosis in tumorigenesis, progression, and treatment has garnered increasing attention [14], [19], [23]. Studies have indicated that ferroptosis significantly influences DDP sensitivity in various tumors [11], [12], [24]. However, the role of ferroptosis in OSCC and its relationship with DDP sensitivity have yet to be fully elucidated.

Histone modification is one of the important mechanisms of epigenetic regulation, with histone deacetylation playing a critical role in gene expression regulation [17]. It has emerged as a potential therapeutic target in cancer treatment [22]. SIRT6 is an NAD+ -dependent protein deacetylase involved in various biological processes, including metabolic regulation, DNA repair, and tumorigenesis [5], [8]. Recent studies have shown that SIRT6 influences gene expression by regulating histone deacetylation, thereby affecting the progression of cancer [1]. However, the role of SIRT6 in regulating ferroptosis in OSCC and its relationship with DDP sensitivity has rarely been reported.

Existing literature indicates that circZDBF2 promotes OSCC progression by sponging miRNAs and recruiting CEBPB to upregulate RNF145, thereby activating the NFκB signaling pathway [15]. However, there is limited research on the oncogenic role of the host gene ZDBF2 in OSCC, and few reports exist regarding its implications in OSCC. Therefore, this study aims to further investigate the regulatory role of ZDBF2 in OSCC.

This study first discovered that ZDBF2 interacts with SIRT6 to mediate histone deacetylation of pro-ferroptosis genes, leading to the downregulation of their expression and inhibition of ferroptosis in OSCC cells, thereby reducing the sensitivity of OSCC cells to DDP. This finding not only reveals the critical role of the ZDBF2/SIRT6 axis in the regulation of ferroptosis in OSCC but also provides a new theoretical basis and potential therapeutic target for overcoming DDP resistance in OSCC.

In summary, this study aims to explore the role of ZDBF2 in the regulation of ferroptosis in OSCC and its relationship with DDP sensitivity, providing scientific evidence for a deeper understanding of the molecular mechanisms underlying OSCC and the development of new therapeutic strategies.