Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours.

结直肠癌 (CRC) 需要大量的铁储存，但对 CRC 调节局部铁处理的完整机制知之甚少。在这里，我们证明铁调素在 CRC 中被异位激活。与野生型同窝小鼠相比，在结肠肿瘤上皮中特异性缺乏铁调素的小鼠在散发性 CRC 模型中表现出显着减少的肿瘤数量、负荷和大小，而通过删除铁输出蛋白转运蛋白导致的细胞内铁积累加剧了这些肿瘤参数. 三维患者来源的 CRC 肿瘤肠子的代谢组学分析表明铁在 CRC 中优先用于生产核苷酸，这在我们的 hepcidin/ferroportin 小鼠 CRC 模型中得到了概括。从机制上讲，我们的数据表明铁螯合会降低线粒体功能，从而改变核苷酸合成，而在铁螯合剂存在的情况下，外源性补充核苷或天冬氨酸可部分挽救患者来源的肠样和 CRC 细胞系中的肿瘤生长。总的来说，这些数据表明肿瘤上皮细胞中的异位铁调素建立了一个轴来螯合铁，以维持核苷酸库并维持结直肠肿瘤的增殖。