Abstract
BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common subtype of oral cancer, and its poor prognosis is largely attributed to uncontrolled proliferation, invasion, and therapeutic resistance. Our recent transcriptomic profiling identified that the non-coding RNA (lncRNA) AC007271.3 was markedly upregulated in OSCC compared with paired normal mucosal tissues. This lncRNA may serve as a prognostic biomarker for OSCC, which accelerates tumor progression. However, its underlying mechanisms remain unclear. In this study, we investigated the regulatory mechanism by which cancer-testis long noncoding RNA (CT-lncRNA) AC007271.3 mediates cisplatin resistance through ferroptosis. METHODS: GTEx database was used to reveal that AC007271.3 is a CT-lncRNA. Bioinformatic analysis was employed to analyze differential gene expression and associated pathways after knocking down AC007271.3. Transmission electron microscopy and flow cytometry were used to detect mitochondrial reactive oxygen species (ROS). Wound healing, CCK-8, colony formation, invasion, migration and cell line-derived xenograft (CDX) models were used to assess the proliferation, migration and invasion abilities of cancer cells in vitro and in vivo. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays were conducted to identify and validate the underlying regulatory mechanisms of AC007271.3. RESULTS: Bioinformatics analysis suggested that AC007271.3 is a CT-lncRNA, and transcriptome sequencing confirmed that AC007271.3 may promote OSCC progression by modulating ferroptosis. Mechanistically, AC007271.3 acts as a decoy for MBP-1 to block the binding of MBP-1 to the c-Myc promoter, and thus activating c-Myc transcription, leading to upregulated expression of the ferroptosis regulator GPX4, thereby suppressing ferroptosis and facilitating G1/S transition, which ultimately accelerates tumor progression and chemoresistance. This study identified AC007271.3 as a critical CT-lncRNA that inhibits ferroptosis and leads to cisplatin resistance in OSCC cells, thereby accelerating tumor advancement via the MBP-1/c-Myc/GPX4 axis. CONCLUSIONS: To our knowledge, this is the first study to report that this CT-lncRNA promotes carcinogenesis and that c-Myc directly binds to the GPX4 promoter, thus triggering GPX4 transcription to inhibit ferroptosis in OSCC. These findings highlight AC007271.3 as a potential therapeutic target and provide new insight into the molecular pathogenesis of OSCC. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-026-04281-8.