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<p>Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1’s noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.</p><p></p>

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PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation

  • 期刊论文

  • 发表日期：

    2025年4月25日

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  • Peixiang Zheng,
  • Zhiqiang Hu,
  • Yuli Shen,
  • Lina Gu,
  • Yuan Ouyang,
  • Yuran Duan,
  • Guimei Ji,
  • Bofei Dong,
  • Yanni Lin,
  • Ting Wen,
  • Qi Tian,
  • Yueru Hou,
  • Qimin Zhou,
  • Xue Sun,
  • Xiaohan Chen,
  • Katherine L. Wang,
  • Shudi Luo,
  • Shiqi Wu,
  • Yuening Sun,
  • Min Li,
  • Liwei Xiao,
  • Qingang Wu,
  • Ying Meng,
  • Guijun Liu,
  • Zheng Wang,
  • Xueli Bai,
  • Shengzhong Duan,
  • Yuan Ding,
  • Yanli Bi,
  • Yuhao Wang,
  • Gaopeng Li,
  • Xiaoguang Liu,
  • Zhimin Lu,
  • Xiaohong Wu,
  • Zhiyuan Tang,
  • Daqian Xu

摘要

Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1’s noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.