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

Cell Death & Differentiation volume 32, pages 1058–1070 (2025)Cite this article

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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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Fig. 1: PKA suppresses ferroptosis.
Fig. 2: GPX4 is a critical regulator for PKA-dependent ferroptosis.
Fig. 3: ALKBH5 is a direct phosphorylation substrate of PKA.
Fig. 4: PKA regulates ALKBH5 stability and m6A modification.
Fig. 5: ALKBH5 regulates GPX4-dependent ferroptosis.
Fig. 6: PKA-ALKBH5-GPX4 regulates ferroptosis.
Fig. 7: PKA-ALKBH5-GPX4 regulates tumor growth.

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Acknowledgements

We thank Dr. Pavel I Nedvetsky (University Hospital Münster, Germany) for kindly suggestion. This work was supported by the grants from National Natural Science Foundation of China (82200438, 82200271, 82311530688), the Guangdong Provincial Natural Science Foundation (2022A1515011946), the Guangdong Zhujiang Talent Program (0920220203), Shenzhen Key Laboratory (ZDSYS20230626091402006) Shenzhen Clinical Research Center for Gastroenterology (LCYSSQ20220823091203008), Natural Science Funds of Zhejiang Province (LQ22H020010) and Leading Innovation and Entrepreneurship Team of Zhejiang Province (2023R01005).

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Author notes

  1. These authors contributed equally: Xiaocheng Zhao, Yanxi Sun

Authors and 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

    Xiaocheng Zhao, Yanxi Sun, Juan Zou, Minyi Huang & Huimin Kong

  2. Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China

    Yanxi Sun, Juan Zou, Yanxia Wu, Minyi Huang & Xingwu Wang

  3. School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China

    Guangda Liu & Yunjiao Zhang

  4. 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

    Guangda Liu & Min Shang

  5. VIB Center for the Biology of Disease, VIB, Leuven, Belgium. Center for Human Genetics, School of Medicine, University of Leuven, Leuven, Belgium

    Guangda Liu

  6. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Holger Gerhardt

  7. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany

    Holger Gerhardt

  8. Charité–Universitätsmedizin Berlin, Berlin, Germany

    Holger Gerhardt

  9. 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

    Wei Gu

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  1. Xiaocheng Zhao
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Contributions

Conception and experimental design: XZ, YS, XW. Methodology and data acquisition: YS, XZ, JZ, XW. Analysis and interpretation of data: XZ, YS, JZ, YW, MH, HK, GL, HG, WG, YZ, MS, XW. Manuscript writing: XZ, YZ, MS, XW.

Corresponding authors

Correspondence to Xiaocheng Zhao, Yunjiao Zhang, Min Shang or Xingwu Wang.

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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.

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Zhao, X., Sun, Y., Zou, J. et al. Protein kinase A regulates ferroptosis by controlling GPX4 m6A modification through phosphorylation of ALKBH5. Cell Death Differ 32, 1058–1070 (2025). https://doi.org/10.1038/s41418-025-01453-3

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