结直肠癌（CRC）是美国第三常见的癌症，也是癌症相关死亡的第三大原因。了解CRC的生长和进展机制对于改善治疗至关重要。葡萄糖等宏量营养物质是细胞的能源来源。许多肿瘤细胞表现出增加的有氧糖酵解。在小鼠和人类体内，组织微量营养铁水平的增加也与结肠肿瘤发生增加有关。然而，铁是否通过影响葡萄糖代谢来推动结肠癌发生仍不清楚。在本研究中，我们发现铁处理后，肿瘤结肠细胞内葡萄糖水平显著增加。13C标记葡萄糖通量分析表明，在铁处理后，多个标记糖酵解产物的水平显著增加，而几个三羧酸循环中间产物的水平显著降低。机制研究表明，铁通过直接与坦凯瑞斯（tankyrase）和/或丙酮酸脱氢酶激酶（PDHK）3结合，上调了葡萄糖转运蛋白1（GLUT1）的表达，并介导了丙酮酸脱氢酶（PDH）复合物功能的抑制。抑制GLUT1或PDHK通过重新激活PDH复合物功能，减少了高铁饮食增强的肿瘤形成。总之，过多的铁至少部分通过抑制PDH复合物功能来促进糖酵解和结肠肿瘤生长。© 2023 Elsevier B.V. 版权所有。

Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function.Copyright © 2023 Elsevier B.V. All rights reserved.