Protein kinase A regulates ferroptosis by controlling GPX4 m⁶A modification through phosphorylation of ALKBH5

Xiaocheng Zhao^#¹, Yanxi Sun^#^{2

3}, Juan Zou^{2

3}, Yanxia Wu³, Minyi Huang^{2

3}, Huimin Kong², Guangda Liu^{4

5

6}, Holger Gerhardt^{7

8

9}, Wei Gu¹⁰, Yunjiao Zhang¹¹, Min Shang¹², Xingwu Wang¹³

Affiliations

¹ Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China. zxc@mail.ustc.edu.cn.
² Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
³ Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
⁴ School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China.
⁵ Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
⁶ VIB Center for the Biology of Disease, VIB, Leuven, Belgium. Center for Human Genetics, School of Medicine, University of Leuven, Leuven, Belgium.
⁷ Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁸ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
⁹ Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁰ Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.
¹¹ School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China. zhangyunjiao@scut.edu.cn.
¹² Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. minshang@zju.edu.cn.
¹³ Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China. wxwbio@mail.ustc.edu.cn.

^# Contributed equally.

PMID: 39901038
PMCID: PMC12163066 (available on 2026-06-01)
DOI: 10.1038/s41418-025-01453-3

Protein kinase A regulates ferroptosis by controlling GPX4 m⁶A modification through phosphorylation of ALKBH5

Xiaocheng Zhao et al. Cell Death Differ. 2025 Jun.

. 2025 Jun;32(6):1058-1070.

doi: 10.1038/s41418-025-01453-3. Epub 2025 Feb 3.

Authors

Affiliations

¹ Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China. zxc@mail.ustc.edu.cn.
² Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
³ Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
⁴ School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China.
⁵ Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
⁶ VIB Center for the Biology of Disease, VIB, Leuven, Belgium. Center for Human Genetics, School of Medicine, University of Leuven, Leuven, Belgium.
⁷ Max Delbrück Center for Molecular Medicine, Berlin, Germany.
⁸ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
⁹ Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁰ Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.
¹¹ School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China. zhangyunjiao@scut.edu.cn.
¹² Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. minshang@zju.edu.cn.
¹³ Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China. wxwbio@mail.ustc.edu.cn.

^# Contributed equally.

PMID: 39901038
PMCID: PMC12163066 (available on 2026-06-01)
DOI: 10.1038/s41418-025-01453-3

Abstract

GPX4-dependent ferroptosis has emerged as a therapeutic strategy for cancer treatment. Here, we demonstrated that protein kinase A (PKA) participates in the regulation of ferroptosis by controlling the m⁶A modification of GPX4 in an ALKBH5-dependent manner. Notably, we identified ALKBH5, an m⁶A demethylase, as a novel target of PKA, which drives phosphorylation-dependent degradation of ALKBH5 protein. Moreover, the deletion of ALKBH5 represses ferroptotic cell death by maintaining GPX4 m⁶A modification and stability. Thus, by regulating ALKBH5-dependent GPX4 stability, PKA acts as a key regulator of ferroptosis. Our study unveils the involvement of PKA in m⁶A modification, which could control GPX4-dependent ferroptosis and tumor progression.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval: All experiments with animals were approved by the Animal Care and Use Committee (IACUC), Sun Yat-sen University (Approve number: SYSU-IACUC-2024-000478) and performed according to the relevant ethical guidelines and regulations. This research did not involve human subject study.

References

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Protein kinase A regulates ferroptosis by controlling GPX4 m⁶A modification through phosphorylation of ALKBH5

Affiliations

Protein kinase A regulates ferroptosis by controlling GPX4 m⁶A modification through phosphorylation of ALKBH5

Authors

Affiliations

Abstract

Conflict of interest statement

References

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