氨基酸半胱氨酸及其氧化二聚体半胱氨酸被普遍认为在代谢功能上具有同义性。半胱氨酸缺乏不仅引起氨基酸反应，而且还触发非凋亡细胞死亡方式的铁死亡。在这里，我们报告了与一般氨基酸饥饿不同的是，缺乏半胱氨酸引起转录水平上的ATF4诱导。出乎意料的是，是溶酶体内半胱氨酸短缺而不是细胞质内半胱氨酸引发了适应性ATF4反应。溶酶体-核信号途径涉及芳香烃受体（AhR），通过吲哚酮途径感知溶酶体内的半胱氨酸。阻断溶酶体内半胱氨酸外流会削弱ATF4诱导并增加对铁死亡的敏感性。为了增强癌症中的铁死亡，我们开发了一种合成mRNA试剂CysRx，将细胞质内的半胱氨酸转化为溶酶体内的半胱氨酸。CysRx最大程度地促进了癌细胞中的铁死亡，并有效抑制了体内肿瘤生长。因此，细胞内营养再编程具有在癌症中诱导选择性铁死亡而不引起全身饥饿的潜力。版权所有© 2023 Elsevier Inc. 保留所有权利。

The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.Copyright © 2023 Elsevier Inc. All rights reserved.