Glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma by downregulating GLUD1 and promoting ROS-mediated inhibition of Wnt/β-catenin signaling.
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Osteosarcoma is a highly malignant primary bone tumor that predominantly affects children and adolescents. Although chemotherapy has significantly improved overall survival, drug resistance remains a major cause of poor prognosis. Current studies largely focus on isolated signaling events and still lack a systematic understanding of the coordinated interplay among metabolic reprogramming, redox homeostasis, and cell death, thereby limiting translational relevance and the identification of effective therapeutic targets. The present study aimed to investigate how glutamine regulates reactive oxygen species (ROS) levels in osteosarcoma cells and to clarify the mechanism by which the Wnt/β-catenin pathway influences doxorubicin sensitivity. The effects of glutamine metabolism on osteosarcoma chemosensitivity were systematically evaluated using both in vitro and in vivo models. Integrated transcriptomic analysis was further performed to identify key metabolic and signaling regulators associated with redox balance and chemosensitivity. The results showed that glutamine deprivation or L-asparaginase treatment significantly enhanced the sensitivity of HOS, MNNG, and their doxorubicin-resistant derivatives to doxorubicin, as evidenced by reduced cell proliferation and increased expression of the apoptosis-related proteins Bax and cleaved caspase-3. Glutamine depletion also increased intracellular ROS levels, decreased glutathione content and mitochondrial membrane potential, altered cellular glycolytic status, and downregulated GLUD1 expression. Similarly, GLUD1 silencing recapitulated these effects, whereas NAC treatment partially reversed them. Moreover, both glutamine deprivation and ROS accumulation suppressed activation of Wnt/β-catenin signaling. In vivo, the combination of L-asparaginase and doxorubicin, as well as treatment with XAV-939, significantly inhibited tumor growth, whereas NAC attenuated these effects. In conclusion, glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma. Mechanistically, this chemosensitizing effect is mediated by downregulation of GLUD1, which promotes intracellular ROS accumulation and subsequently suppresses Wnt/β-catenin signaling.