DKK1 Promotes Cisplatin Resistance in Oral Squamous Cell Carcinoma via SLC3A2 ‐Dependent Ferroptosis Suppression

ABSTRACT Background Oral squamous cell carcinoma (OSCC) is a prevalent malignancy associated with poor outcomes, largely attributable to cisplatin resistance—the standard chemotherapeutic agent. Aims While ferroptosis has been proposed as a promising therapeutic target, how it is regulated in OSCC remains largely unclear. Methods and Results To determine DKK1 expression levels and their prognostic implication, the TCGA‐HNSC cohort and OSCC patient samples were examined. The impact of DKK1 silencing and/or cisplatin treatment on cell proliferation and ferroptosis‐related markers, including reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels, was investigated in vitro. Additionally, the efficacy of DKK1 inhibition was evaluated in xenograft models. The findings revealed that DKK1 expression was markedly elevated in the TCGA‐HNSC cohort and was further validated in OSCC tissues. High DKK1 expression was associated with worse survival and contributed to cisplatin resistance, while DKK1 silencing sensitized cells to ferroptosis and enhanced cisplatin cytotoxicity. Mechanistically, our data support a regulatory model in which DKK1 maintains SLC3A2 expression through modulation of the β‐catenin/STAT3 axis, thereby contributing to ferroptosis suppression and cisplatin resistance. In vivo, DKK1 inhibition improved cisplatin efficacy, at least in part, by promoting SLC3A2‐associated ferroptosis. Conclusion These findings support DKK1 as a potential regulator of ferroptosis and cisplatin resistance in OSCC. Targeting the DKK1/SLC3A2 axis to restore ferroptotic sensitivity may represent a promising strategy to overcome chemoresistance.