<p>Our previous study has identified that PRELP inhibits the progression of oral squamous cell carcinoma (OSCC). This study aimed to investigate the influence of PRELP on cisplatin (DDP) resistance in OSCC cells and to elucidate the underlying mechanism. The levels of PRELP, miR-3127-5p, and GAS5 in established DDP-resistant OSCC cell lines (CAL27/DDP and SCC-15/DDP) and parental cells were detected. Following transfection with PRELP overexpressing or silencing plasmids in DDP-resistant OSCC cells, DDP resistance was evaluated by the IC50 values, proliferation, apoptosis and ABCB1 expression. Bioinformatic analysis, dual-luciferase reporter assays, and rescue experiments were employed to explore the upstream miRNA and lncRNA of PRELP. Our results demonstrated that in both DDP-resistant cells, PRELP and GAS5 levels were decreased, while miR-3127-5p expression was increased compared with parental cells. PRELP overexpression reduced the IC50 of DDP and EdU-positive cell number, enhanced cell apoptosis, and suppressed ABCB1 expression in resistant cells. Conversely, PRELP silencing caused opposite effects. In the TCGA database, miR-3127-5p was highly expressed in HNSC, and patients with higher miR-3127-5p expression had shorter overall survival. A negative correlation was observed between miR-3127-5p and PRELP in HNSC. miR-3127-5p promoted DDP resistance in OSCC by targeting PRELP. GAS5 positively modulated PRELP expression by sponging miR-3127-5p. The alleviation of DDP resistance by GAS5 was attenuated by miR-3127-5p mimic and PRELP downregulation. In conclusion, PRELP, which is regulated by lncRNA GAS5/miR-3127-5p axis, suppresses DDP resistance in OSCC through decreasing ABCB1 expression. Targeting the GAS5/miR-3127-5p/PRELP axis may offer a promising strategy to overcome DDP resistance in OSCC.</p>