System Xc^- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma

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.