Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling

IDO1 oxidizes tryptophan (TRP) to generate kynurenine (KYN), the substrate for 1-carbon metabolism and NAD biosynthesis and is implicated in pro-cancer pathophysiology and infection biology. However, the mechanistic relationships between IDO1 in amino acid depletion versus product generation have remained a long-standing mystery. We found an unrecognized link between IDO1 and cell survival mediated by KYN that serves as the source for molecules that inhibit ferroptotic cell death. We show this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression. Whether inside the “producer” IDO1+ cell or the “receiver” cell, KYN is converted into downstream metabolites, suppressing ferroptosis by ROS scavenging and activating an NRF2-dependent, AHR-independent cell protective pathway, including SLC7A11, which further propagates anti-ferroptotic signaling. IDO1 therefore controls a multi-pronged protection pathway from ferroptotic cell death, underscoring the need to re-focus the clinical use of IDO1 inhibitors in cancer.吲哚胺2,3-双加氧酶1（Indoleamine 2,3-Dioxygenase 1，IDO1）可将色氨酸（tryptophan, TRP）氧化生成犬尿氨酸（kynurenine, KYN）——KYN是一碳代谢与烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD）生物合成的底物，且其与促癌病理生理学及感染生物学密切相关。然而，IDO1介导的氨基酸耗竭与产物生成之间的机制关联，长期以来仍是一个未解之谜。本研究发现了一条此前未被阐明的关联通路：IDO1可通过KYN介导调控细胞存活，而KYN可作为抑制铁死亡（ferroptosis）的分子来源。我们证实，该效应依赖于KYN从表达IDO1的细胞中输出，随后未表达IDO1的细胞可通过溶质载体家族7成员11（solute carrier family 7 member 11, SLC7A11）获取KYN——该转运蛋白是铁死亡抑制的核心调控因子。无论是在“产生者”IDO1阳性细胞还是“接收者”细胞内部，KYN都会被转化为下游代谢产物，通过清除活性氧（reactive oxygen species, ROS）并激活一条依赖于核因子E2相关因子2（nuclear factor erythroid 2-related factor 2, NRF2）且不依赖于芳香烃受体（aryl hydrocarbon receptor, AHR）的细胞保护通路（其中包含SLC7A11），进而抑制铁死亡；而SLC7A11可进一步放大抗铁死亡信号转导。因此，IDO1可调控一条多维度的抗铁死亡细胞保护通路，这一发现强调了重新审视IDO1抑制剂在癌症临床应用中的必要性。