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Background <p>Triptolide, the active compound of <i>Tripterygium wilfordii</i>, exhibits broad anti-tumor activity. This study explores <i>PPP2CA</i> dysregulation in ovarian cancer (OC) progression via lactate production and evaluates Triptolide’s potential to regulate this process.</p> Methods <p>We used patient-derived xenograft (PDX) models, cell proliferation, and migration assays to assess lactate’s impact on OC progression. CRISPR-Cas9 was applied to knock out <i>PPP2CA</i>, examining its effect on lactate production and tumor progression. RNA-seq analyzed transcriptomic changes post-<i>PPP2CA</i> knockout. The <i>PPP2CA-ITGA5</i> axis was validated using xenografts, immunofluorescence, immunohistochemistry staining and western blot. Exosome isolation and co-culture experiments with tumor cells and human peritoneal mesothelial cells (HPMCs) investigated <i>ITGA5</i>’s role in migration. Finally, patient-derived organoids, xenograft tumor model, and lactate assays assessed Triptolide’s reversal effect on <i>PPP2CA</i> dysregulation-driven OC progression.</p> Results <p>We found that <i>PPP2CA</i> dysregulation significantly promotes OC proliferation, migration, and tumorigenesis by enhancing <i>YAP</i> nuclear translocation and upregulating <i>ITGA5/ITGB1</i>. <i>PPP2CA</i> dysregulation led to <i>ITGA5</i> upregulation, where <i>ITGA5</i>, as part of the <i>integrin α5β1</i> heterodimer, plays a key role in driving OC migration. Exosomal <i>ITGA5</i> facilitates OC metastasis to the HPMCs. Triptolide effectively inhibited patient-derived organoid growth and reduced lactate production in OC cells. By suppressing <i>ITGA5</i>, Triptolide reversed cancer progression and restored tumor-suppressive effects in a <i>PPP2CA</i>-knockout xenograft model.</p> Conclusion <p>Our study reveals that Triptolide effectively inhibits OC progression by targeting the <i>PPP2CA-ITGA5</i> axis, mitigating lactate-driven metabolic reprogramming.</p> Graphic Abstract <p></p>

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Triptolide targets PPP2CA/ITGA5 axis to suppress lactate-driven ovarian cancer progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月6日

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  • Ling Ding,
  • Wutao Chen,
  • Cenxin Luo,
  • Nathaniel Weygant,
  • Yi Lai,
  • Dan Ru,
  • Hengan Liu,
  • You Wang,
  • He Li

摘要

Background

Triptolide, the active compound of Tripterygium wilfordii, exhibits broad anti-tumor activity. This study explores PPP2CA dysregulation in ovarian cancer (OC) progression via lactate production and evaluates Triptolide’s potential to regulate this process.

Methods

We used patient-derived xenograft (PDX) models, cell proliferation, and migration assays to assess lactate’s impact on OC progression. CRISPR-Cas9 was applied to knock out PPP2CA, examining its effect on lactate production and tumor progression. RNA-seq analyzed transcriptomic changes post-PPP2CA knockout. The PPP2CA-ITGA5 axis was validated using xenografts, immunofluorescence, immunohistochemistry staining and western blot. Exosome isolation and co-culture experiments with tumor cells and human peritoneal mesothelial cells (HPMCs) investigated ITGA5’s role in migration. Finally, patient-derived organoids, xenograft tumor model, and lactate assays assessed Triptolide’s reversal effect on PPP2CA dysregulation-driven OC progression.

Results

We found that PPP2CA dysregulation significantly promotes OC proliferation, migration, and tumorigenesis by enhancing YAP nuclear translocation and upregulating ITGA5/ITGB1. PPP2CA dysregulation led to ITGA5 upregulation, where ITGA5, as part of the integrin α5β1 heterodimer, plays a key role in driving OC migration. Exosomal ITGA5 facilitates OC metastasis to the HPMCs. Triptolide effectively inhibited patient-derived organoid growth and reduced lactate production in OC cells. By suppressing ITGA5, Triptolide reversed cancer progression and restored tumor-suppressive effects in a PPP2CA-knockout xenograft model.

Conclusion

Our study reveals that Triptolide effectively inhibits OC progression by targeting the PPP2CA-ITGA5 axis, mitigating lactate-driven metabolic reprogramming.

Graphic Abstract