Abstract

Objective and Background Oral squamous cell carcinoma (OSCC) is a common and aggressive malignant tumor. The circular RNA circZDBF2 derived from ZDBF2 is identified as an oncogenic factor in OSCC, but the role of ZDBF2 remains unclear. This study investigates the function of ZDBF2 in OSCC, especially its impact on cisplatin (DDP) sensitivity. Methods The expression of ZDBF2 in head and neck squamous cell carcinoma (HNSC) was analyzed using online databases and validated in OSCC cells via RT-qPCR and Western blot. To assess the effect of ZDBF2 on DDP sensitivity, CCK-8 and PI staining assays were performed. The mechanism of ZDBF2-mediated ferroptosis was explored by measuring intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Co-immunoprecipitation (Co-IP), luciferase reporter, and chromatin immunoprecipitation (ChIP) assays were conducted to analyze the relationship between ZDBF2 and ferroptosis-related genes, as well as the role of SIRT6 in this regulation. A mouse model was constructed to validate the role of ZDBF2 in tumor growth. Results ZDBF2 is highly expressed in OSCC cells and significantly inhibits ferroptosis, thereby reducing cell sensitivity to DDP. ZDBF2 regulates the transcription of ferroptosis-related genes through mechanisms independent of direct promoter binding and forms a complex with SIRT6, inhibiting the expression of ferroptosis-related genes via its deacetylation role. Additionally, animal experiments further confirmed the promoting effect of ZDBF2 on tumor growth. Conclusions This study highlights the role of ZDBF2 in OSCC, promoting tumor progression by inhibiting ferroptosis and reducing drug sensitivity, suggesting ZDBF2 as a potential therapeutic target.