BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common malignancy of the nasopharynx. Ferroptosis induction shows anti-tumor activities in cancers including NPC. Elucidating the regulatory mechanism of ferroptosis is crucial for developing targeted therapeutic strategies for NPC. METHODS: The GEO dataset (GSE68799) was used to analyze HOXA9 expression in NPC. Cell viability, levels of MDA, total iron, Fe RESULTS: HOXA9 was highly expressed in NPC, and knockdown of HOXA9 elevated total iron, Fe CONCLUSION: O-GlcNAc-modified HOXA9 inhibits ferroptosis by enhancing UBR5 expression and ubiquitination and degradation of SIRT6 in NPC cells, thus accelerating NPC progression. Our study provides potential therapeutic targets for NPC treatment.