新出现的证据表明，葡萄糖消耗（GD）诱导的细胞死亡取决于Xc-系统，这是一种在铁死亡中广泛研究的谷氨酸/胱氨酸逆向转运蛋白。然而，其根本机制仍存在争议。我们的研究证实了系统Xc和GD诱导的细胞死亡之间的相关性，并为口腔鳞状细胞癌（OSCC）提供了策略性治疗。采用qPCR和Western blotting检测葡萄糖戒断后xCT和CD98表达的变化。然后，测量指定条件下 OSCC 的细胞活力。为了鉴定 SLC7A11 的 GD 响应转录因子，我们进行了荧光素酶报告基因测定和 ChIP 测定。此外，进行代谢组学以确定代谢物的变化。最后，使用海马测定评估线粒体功能和 ATP 产生，并使用 NADP /NADPH 试剂盒测量 NADP /NADPH 动态。在 OSCC 中，系统 Xc- 通过增加谷氨酸消耗来促进 GD 诱导的细胞死亡，从而促进 NADPH 耗尽和TCA封锁。此外，GD 诱导的 xCT 上调受 p-eIF2α/ATF4 轴控制。系统 Xc 过度表达损害了 GD 条件下 OSCC 的代谢灵活性，因此，葡萄糖饥饿疗法可有效杀死 OSCC 细胞。© 2023 Wiley periodicals LLC 。

Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc- , a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC).qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+ /NADPH dynamics were measured using a NADP+ /NADPH kit.In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis.System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.© 2023 Wiley Periodicals LLC.