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Background <p>Endometrial carcinoma (EC) is an aggressive gynecological malignancy with high recurrence rates and limited treatment options. Patients with EC exhibit elevated serum levels of lyso-platelet-activating factor (lyso-PAF), a biologically inactive product generated during the hydrolysis of PAF by PAF-acetylhydrolase (II) (PAF-AH2). Nevertheless, the biological function of PAF in EC progression and the relationship between abnormal lyso-PAF levels and EC progression remain unclear.</p> Results <p>In this study, we identified the bioactive phospholipid mediator–PAF, which effectively suppress tumor growth both in vitro and in patient-derived organoid models. By combining the cellular thermal shift assay, drug affinity responsive target stability approach, molecular docking simulation, and surface plasmon resonance analysis, we identified activating transcription factor 3 (ATF3) as the direct binding target of PAF with a Kd of 3 0.24 µM. Mechanistically, PAF enhanced ATF3 stability through deubiquitination. In addition, ATF3 knockdown partially reversed the effects of PAF-induced <i>SLC7A11</i> and <i>GPX4</i> transcriptional inhibition. In vivo studies using a nude mouse xenograft model confirmed the ferroptosis-mediated tumor-suppressive effects of PAF, as evidenced by hematoxylin and eosin staining and immunohistochemical analysis. Clinically, proteomic analysis revealed upregulation of PAF-AH2 expression in EC tissues derived from patients. Subsequent analysis of EC tissue microarrays revealed that high PAF-AH2 expression is associated with poor survival.</p> Conclusions <p>In conclusion, this study demonstrates that PAF inhibits EC tumor growth by inducing ferroptosis and that the underlying mechanisms of its action involve the targeting of ATF3. These findings suggest that PAF metabolism may be a promising direction for EC diagnostics and therapeutics.</p>

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Platelet-activating factor induces ferroptosis by binding to ATF3 and inhibiting the SLC7A11/GPX4 axis to suppress the progression of endometrial carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Feifei Pan,
  • Yuqing Qiu,
  • Zhuojie Huang,
  • Yanqin Zheng,
  • Yun Chen,
  • Yiming Song,
  • Zhe-Sheng Chen,
  • Lirong Guo,
  • Jingyao Wang,
  • Xiaojie Liu,
  • Zixin Tao,
  • Yaqiong Liu,
  • Xingcui Xuan,
  • Kunxiang Gong,
  • Kun Shi

摘要

Background

Endometrial carcinoma (EC) is an aggressive gynecological malignancy with high recurrence rates and limited treatment options. Patients with EC exhibit elevated serum levels of lyso-platelet-activating factor (lyso-PAF), a biologically inactive product generated during the hydrolysis of PAF by PAF-acetylhydrolase (II) (PAF-AH2). Nevertheless, the biological function of PAF in EC progression and the relationship between abnormal lyso-PAF levels and EC progression remain unclear.

Results

In this study, we identified the bioactive phospholipid mediator–PAF, which effectively suppress tumor growth both in vitro and in patient-derived organoid models. By combining the cellular thermal shift assay, drug affinity responsive target stability approach, molecular docking simulation, and surface plasmon resonance analysis, we identified activating transcription factor 3 (ATF3) as the direct binding target of PAF with a Kd of 3 0.24 µM. Mechanistically, PAF enhanced ATF3 stability through deubiquitination. In addition, ATF3 knockdown partially reversed the effects of PAF-induced SLC7A11 and GPX4 transcriptional inhibition. In vivo studies using a nude mouse xenograft model confirmed the ferroptosis-mediated tumor-suppressive effects of PAF, as evidenced by hematoxylin and eosin staining and immunohistochemical analysis. Clinically, proteomic analysis revealed upregulation of PAF-AH2 expression in EC tissues derived from patients. Subsequent analysis of EC tissue microarrays revealed that high PAF-AH2 expression is associated with poor survival.

Conclusions

In conclusion, this study demonstrates that PAF inhibits EC tumor growth by inducing ferroptosis and that the underlying mechanisms of its action involve the targeting of ATF3. These findings suggest that PAF metabolism may be a promising direction for EC diagnostics and therapeutics.