Zhan Jiani, Chen Yijia, Liu Yuying, Chen Yunqiu, Li Zhiyao, Li Xuewen, He Zhenning, Meng Fangzhou, Qian Xiaoyang, Yang Lili, Yang Qing
State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China.
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
Biochem Pharmacol. 2025 Jun;236:116913. doi: 10.1016/j.bcp.2025.116913. Epub 2025 Mar 29.
Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.
铁死亡是一种以铁依赖性脂质过氧化物积累为特征的细胞死亡方式。吲哚胺2,3-双加氧酶1（IDO1）是色氨酸通过犬尿氨酸途径分解代谢的关键酶，参与多种肿瘤类型的发展。然而，IDO1在肿瘤铁死亡中的作用尚不清楚。在本研究中，我们确定IDO1是肺癌铁死亡的关键调节因子。在用埃拉斯汀处理的肺癌细胞中，我们发现IDO1抑制铁死亡，减少脂质过氧化物和活性氧的产生。机制上，IDO1通过激活芳烃受体（AhR）途径促进核因子红细胞2相关因子2（NRF2）的表达。IDO1通过AhR-NRF2轴上调溶质载体家族7成员11（SLC7A11）的表达和磷酸戊糖途径（PPP）的活性，促进还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和谷胱甘肽（GSH）的产生，从而抑制铁死亡。此外，IDO1抑制剂与埃拉斯汀联合治疗可抑制荷肺癌小鼠的肿瘤生长，下调SLC7A11表达和PPP活性，促进肿瘤铁死亡。总之，本研究揭示了IDO1在肺癌铁死亡中的作用，为肺癌治疗提供了新策略。
