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In biological systems, iron is present in either reduced (Fe<jats:sup>2+<\/jats:sup>; ferrous) or oxidized (Fe<jats:sup>3+<\/jats:sup>; 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\u2013IRP2 axis, a ubiquitin\u2010dependent 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\u2010dependent 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\u2010bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth.<\/jats:p>","DOI":"10.1111\/cas.15949","type":"journal-article","created":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T05:21:28Z","timestamp":1694236888000},"page":"4355-4364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Distinct functions between ferrous and ferric iron in lung cancer cell growth"],"prefix":"10.1111","volume":"114","author":[{"given":"Hironori","family":"Hinokuma","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, Faculty of Life Sciences Kumamoto University  Kumamoto Japan"},{"name":"Department of Thoracic and Breast Surgery, Graduate School of Medical Sciences Kumamoto University  Kumamoto 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