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

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