Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation.

正常细胞和转化细胞都需要半胱氨酸来维持细胞氧化还原稳态。半胱氨酸的缺乏会诱导铁依赖性细胞死亡，称为铁死亡。然而，除了谷胱甘肽合成受损之外，半胱氨酸饥饿的代谢后果尚不清楚。在这里，我们发现非小细胞肺癌细胞系的胱氨酸饥饿会诱导γ-谷氨酰肽的意外积累，这是由于谷氨酸半胱氨酸连接酶催化亚基（GCLC）的非典型活性而产生的。这种活性在具有高水平 NRF2（GCLC 的关键转录调节因子）的细胞系中富集，但在半胱氨酸限制后的健康小鼠组织中也可诱导。 γ-谷氨酰肽合成限制谷氨酸的积累，从而防止铁死亡。这些结果表明，GCLC 在胱氨酸饥饿下通过维持谷氨酸稳态来防止铁死亡，具有不依赖于谷胱甘肽的非经典作用。