越来越多的证据表明铁代谢与肺癌进展之间存在关联。在生物系统中，铁以还原态（Fe2+；亚铁）或氧化态（Fe3+；三价铁）存在。然而，亚铁和三价铁具有不同的化学和生物学特性，亚铁和三价铁在肺癌细胞生长中的作用尚未明确区分。在本研究中，我们通过诱导涉及FBXL5-IRP2轴的基因突变来操纵细胞内亚铁和三价铁的平衡状态，该轴是细胞铁稳态的泛素依赖调控系统，并确定其对肺癌细胞生长的影响。研究发现，FBXL5缺失（亚铁积累）抑制了肺癌细胞的生长，而IRP2缺失（三价铁积累）并未抑制该生长，表明亚铁而非三价铁在细胞生长中发挥了抑制作用。从机制上讲，FBXL5的缺失影响了细胞周期G1/S期间的周期依赖性激酶抑制剂p27的降解，导致细胞周期延迟。肺癌细胞中的FBXL5缺失还改善了肿瘤鼠的生存。总的来说，本研究强调了亚铁在细胞周期进展和肺癌细胞生长中的重要功能。© 2023 The Authors. 由约翰·威利父子澳大利亚有限公司代表日本癌症协会发表的《癌症科学》。

Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe2+ ; ferrous) or oxidized (Fe3+ ; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5-IRP2 axis, a ubiquitin-dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin-dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor-bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth.© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.