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 uncharacterized. Here, we find that cystine starvation promotes ferroptosis not only through the inhibition of glutathione (GSH) synthesis, but also through the accumulation of glutamate. Surprisingly, we find that glutamate-cysteine ligase catalytic subunit (GCLC) prevents glutamate accumulation through the generation of alternative γ-glutamyl peptides. Further, inhibition of GCLC accelerates ferroptosis under cystine starvation in a GSH-independent manner. These results indicate that GCLC has an additional, non-canonical role in the protection against ferroptosis to maintain glutamate homeostasis under cystine starvation.

中文翻译：

---

非规范的谷氨酸-半胱氨酸连接酶活性可预防肥大症

半胱氨酸是维持正常细胞和转化细胞中细胞氧化还原稳态所必需的。剥夺半胱氨酸会导致铁依赖的细胞死亡形式，称为铁锈病。然而，半胱氨酸饥饿的代谢后果超出了谷胱甘肽合成的损害，目前尚无定论。在这里，我们发现胱氨酸饥饿不仅通过抑制谷胱甘肽（GSH）的合成，而且通过谷氨酸的积累来促进肥大症。令人惊讶地，我们发现谷氨酸-半胱氨酸连接酶催化亚基（GCLC）通过产生替代的γ-谷氨酰肽来防止谷氨酸积累。此外，对GCLC的抑制以非GSH依赖性的方式促进胱氨酸饥饿下的肥大化。这些结果表明，GCLC还具有其他功能，