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Journal of Cancer Prevention


J Cancer Prev 2021; 26(4): 244-249

Published online December 30, 2021

© Korean Society of Cancer Prevention

Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles

Shinya Toyokuni1,2 , Yingyi Kong1 , Hao Zheng1 , Danyang Mi1 , Misako Katabuchi1 , Yashiro Motooka1 , Fumiya Ito1

1Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 2Center for Lowtemperature Plasma Sciences, Nagoya University, Nagoya, Japan

Correspondence to :
Shinya Toyokuni, E-mail:,

Received: November 19, 2021; Revised: December 8, 2021; Accepted: December 14, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Human epidemiological and animal studies have demonstrated that excess iron is a risk for cancer. The responsible mechanisms are: 1) increased intracellular iron catalyzes the Fenton reaction to generate hydroxyl radicals, leading to mutagenic oxidative DNA lesions; 2) iron is necessary for cellular proliferation as cofactors of many enzymes. Thus, iron-excess milieu promotes selecting cellular evolution to ferroptosis-resistance, a major basis for carcinogenesis. Ferritin is a 24-subunit nanocage protein required for iron storage under the regulation of the iron-regulatory protein (IRP)/iron-responsive element (IRE) system. Ferritin is a serum marker, representing total body iron storage. However, how ferritin is secreted extracellularly has been unelucidated. We recently discovered that an exosomal marker CD63 is regulated by the IRP/IRE system and that iron-loaded ferritin is secreted as extracellular vesicles under the guidance of nuclear receptor coactivator 4 (NCOA4). On the other hand, we found that macrophages under asbestos-induced ferroptosis emit ferroptosis-dependent extracellular vesicles (FedEVs), which are received by nearby mesothelial cells, resulting in significant mutagenic DNA damage. Therefore, cells, including macrophages, can share excess iron with other cells, via iron-loaded ferritin packaged in extracellular vesicles as safe non-catalytic iron. However, similar process, such as one involving FedEVs, may cause accumulation of excess iron in other specific cells, which may eventually promote carcinogenesis.

Keywords: Ferritin, Extracellular vesicles, Iron, Ferroptosis, Asbestos

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