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<p>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 m<sup>6</sup>A modification of GPX4 in an ALKBH5-dependent manner. Notably, we identified ALKBH5, an m<sup>6</sup>A 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 <i>GPX4</i> m<sup>6</sup>A 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 m<sup>6</sup>A modification, which could control GPX4-dependent ferroptosis and tumor progression.</p>

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

  • 期刊论文

  • 发表日期：

    2025年2月3日

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  • Xiaocheng Zhao,
  • Yanxi Sun,
  • Juan Zou,
  • Yanxia Wu,
  • Minyi Huang,
  • Huimin Kong,
  • Guangda Liu,
  • Holger Gerhardt,
  • Wei Gu,
  • Yunjiao Zhang,
  • Min Shang,
  • Xingwu Wang

摘要

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.