Abstract

Background Tongue squamous cell carcinoma (TSCC) prognosis is often poor, largely due to chemotherapy resistance. This study aimed to identify key genes driving cisplatin resistance in TSCC and uncover their mechanisms. Methods We performed next-generation transcriptome sequencing to find genes associated with cisplatin resistance. DNPEP was identified and its clinical relevance was validated using The Cancer Genome Atlas (TCGA) data and patient tumor samples. The functional roles of DNPEP in proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, apoptosis, and cisplatin response were investigated through in vitro and in vivo experiments. Protein interactions and signaling pathways were also examined. Results DNPEP was differentially expressed in TSCC and linked to cisplatin resistance. High DNPEP expression correlated with TSCC occurrence, progression, and poor patient prognosis. Functionally, elevated DNPEP promoted tumor proliferation, EMT, migration, invasion, and cisplatin resistance, while suppressing apoptosis. Mechanistically, DNPEP directly bound to the RACK1 protein, activating the ERK signaling pathway. Conclusions DNPEP plays a critical role in TSCC progression and cisplatin resistance by interacting with RACK1 and activating ERK signaling, highlighting its potential as a therapeutic target to inhibit TSCC and overcome chemotherapy resistance.