Abstract

Osteosarcoma (OS) is a primary bone malignancy characterized by high metastatic potential and poor prognosis. Nudix hydrolase 1 (NUDT1) plays a key role in preventing oxidative DNA damage, yet its functional significance in OS remains to be fully defined. By integrating transcriptomic data from the TARGET, GEO, and an independent cohort from our institution, we found that NUDT1 is significantly upregulated in OS tissues and cell lines. High NUDT1 expression serves as an independent predictor of unfavorable overall survival. Functional assays demonstrated that NUDT1 promotes OS cell proliferation, migration, and invasion in vitro and accelerates tumor growth in vivo. Mechanistically, GSEA indicated that NUDT1 is associated with metabolic pathways including glycolysis and glutathione metabolism. We confirmed that NUDT1 maintains OS cell fitness by restraining ROS accumulation and limiting oxidative DNA damage, effects that were partially reversed by the antioxidant N-acetyl-L-cysteine (NAC). Furthermore, NUDT1 expression levels were found to correlate with the tumor immune microenvironment, specifically showing associations with the infiltration levels of CD8 + T cells and Naïve B cells. Finally, drug sensitivity profiling and experimental validation suggested that NUDT1 levels may predict response to topoisomerase inhibitors, such as Topotecan and Irinotecan. In conclusion, NUDT1 is a key oncogenic factor involved in redox homeostasis and is closely associated with the immune microenvironment in OS, representing a potential prognostic biomarker and therapeutic target.