AAK1 activation-mediated iron trafficking drives ferroptotic cell death

Ferrous iron is necessary for the occurrence of ferroptosis. The molecular mechanisms that maintain iron homeostasis within cells play a crucial role in the regulation of ferroptosis. However, how cells regulate iron uptake during ferroptosis remains unclear. Here, PKCβII is identified as a key kinase mediating transferrin receptor 1 (TFR1) endocytosis through phosphorylation and activation of AP2-associated protein kinase 1 (AAK1) during the ferroptotic process. Mechanistically, activated AAK1 phosphorylates AP2M1, which facilitates the recruitment of clathrin to mediate the endocytosis of TFR1, increasing the levels of both cellular total iron and ferrous iron and thereby promoting ferroptosis. The non-phosphorylatable mutation of AAK1 inhibits ferroptosis and consequently promotes breast tumor growth in vivo. In conclusion, we identify that the PKCβII-AAK1-AP2M1 pathway is a crucial mechanism for the regulation of cellular iron uptake during ferroptosis, which is correlated with the prognosis of breast cancer patients and presents a potential target for cancer therapy.

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Publication Details

Journal
Nature Communications
Published
2025-12-17
DOI
https://doi.org/10.1038/s41467-025-67523-9
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
0.00

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article

AAK1 activation-mediated iron trafficking drives ferroptotic cell death

Xian-Ying Zhu, Qiaqia Li, Ying Xiao, Xiao‐Feng Zhu et al.
Nature Communications
Ferroptosis and cancer prognosis
article

AAK1 activation-mediated iron trafficking drives ferroptotic cell death

Xian-Ying Zhu, Qiaqia Li, Ying Xiao, Xiao‐Feng Zhu, Hai‐Liang Zhang, Rong Deng, Zhipeng Ye, Linyu Wu, Bingxin Hu, Dong Yang, Jīng Li, Shan Liu, Yuhong Chen, Zhi‐Ling Li, Gong-Kan Feng, Yu-Feng Zhou, Lichao Li, Huailiang Wu, Jia‐Hong Tang, Yi-Qing Guo
article en

Abstract

Ferrous iron is necessary for the occurrence of ferroptosis. The molecular mechanisms that maintain iron homeostasis within cells play a crucial role in the regulation of ferroptosis. However, how cells regulate iron uptake during ferroptosis remains unclear. Here, PKCβII is identified as a key kinase mediating transferrin receptor 1 (TFR1) endocytosis through phosphorylation and activation of AP2-associated protein kinase 1 (AAK1) during the ferroptotic process. Mechanistically, activated AAK1 phosphorylates AP2M1, which facilitates the recruitment of clathrin to mediate the endocytosis of TFR1, increasing the levels of both cellular total iron and ferrous iron and thereby promoting ferroptosis. The non-phosphorylatable mutation of AAK1 inhibits ferroptosis and consequently promotes breast tumor growth in vivo. In conclusion, we identify that the PKCβII-AAK1-AP2M1 pathway is a crucial mechanism for the regulation of cellular iron uptake during ferroptosis, which is correlated with the prognosis of breast cancer patients and presents a potential target for cancer therapy.

Nature CommunicationsVol. 17(1)
Sun Yat-sen University (CN), Guangzhou Women and Children Medical Center (CN), Guangdong Academy of Medical Sciences (CN), Sun Yat-sen University Cancer Center (CN), Guangzhou Medical University (CN)
National Science Foundation, National Natural Science Foundation of China, Science Fund for Creative Research Groups
Openalex Percentile: Top 41%
Ferroptosis and cancer prognosis
DOIOpen Access PDFOpenAlex
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