Ferroptosis is an iron-dependent form of regulated cell death linking iron, lipid, and glutathione levels to degenerative processes and tumor suppression. By performing a genome-wide activation screen, we identified a cohort of genes antagonizing ferroptotic cell death, including GTP cyclohydrolase-1 (GCH1) and its metabolic derivatives tetrahydrobiopterin/dihydrobiopterin (BH4/BH2). Synthesis of BH4/BH2 by GCH1-expressing cells caused lipid remodeling, suppressing ferroptosis by selectively preventing depletion of phospholipids with two polyunsaturated fatty acyl tails. GCH1 expression level in cancer cell lines stratified susceptibility to ferroptosis, in accordance with its expression in human tumor samples. The GCH1-BH4-phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH4, abundance of CoQ10, and peroxidation of unusual phospholipids with two polyunsaturated fatty acyl tails. This demonstrates a unique mechanism of ferroptosis protection that is independent of the GPX4/glutathione system.

中文翻译：

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GTP环水解酶1 /四氢生物蝶呤通过脂质重塑抵消肥大症。

Ferroptosis是铁依赖性形式的受调节的细胞死亡，将铁，脂质和谷胱甘肽水平与退化过程和肿瘤抑制联系在一起。通过执行全基因组激活筛选，我们确定了一组拮抗铁质肥大细胞死亡的基因，包括GTP环水解酶-1（GCH1）及其代谢衍生物四氢生物蝶呤/二氢生物蝶呤（BH4 / BH2）。表达GCH1的细胞合成BH4 / BH2引起脂质重塑，通过选择性地防止具有两个多不饱和脂肪酰基尾巴的磷脂消耗来抑制肥大病。根据其在人类肿瘤样品中的表达，癌细胞系中GCH1的表达水平可分为对肥大症的易感性。GCH1-BH4-磷脂轴可作为抗铁锈病的主要调控因子，控制内源性抗氧化剂BH4的产生，CoQ10的丰度以及具有两个多不饱和脂肪酰基尾巴的不寻常磷脂的过氧化作用。这证明了不受GPX4 /谷胱甘肽系统影响的独特的铁锈病保护机制。