Erianin induces ferroptosis in ovarian cancer cells by upregulating PDP2 and activating the JNK signaling pathway

Purpose: Ovarian Cancer remains the deadliest gynecologic malignancy. Erianin, a plant-derived compound with antitumor activity through inducing ferroptosis-an iron-dependent programmed cell death that has been shown in Other contexts to enhance tumor sensitivity to chemotherapy-has not yet been fully explored in ovarian Cancer. We therefore evaluated its anti-proliferative effects and underlying mechanism.

Methods: Cell viability (CCK-8), cell death (Annexin V-FITC/PI flow cytometry, Western blot), and lipid peroxidation assays were performed in A2780 and ES-2 cells. Transcriptome (RNA-seq) and GO enrichment analyses identified signaling pathways, followed by mechanistic validation. Antitumor efficacy was verified in a nude-mouse xenograft model.

Results: Erianin exhibited a dose-dependent inhibitory effect on the proliferation of ovarian Cancer cells A2780 and ES-2. Ferroptosis was identified as the primary mode of cell death, supported by a combination of evidence: (i) preferential rescue with the Ferroptosis inhibitor Ferrostatin-1; (ii) characteristic molecular changes, including downregulation of key suppressors (GPX4, FTH1, SLC7A11) and upregulation of the pro-ferroptotic protein ACSL4; and (iii) elevated lipid peroxidation (MDA) and ROS alongside depleted GSH. Annexin V-FITC/PI flow cytometry was used to assess overall cell death patterns. Mechanistic studies showed that Erianin promoted Ferroptosis via activation of the JNK signaling pathway and upregulation of PDP2 expression. In vivo, Erianin significantly suppressed tumor growth and induced molecular changes indicative of a less aggressive phenotype, including modulation of epithelial-mesenchymal transition (EMT) markers (increased E-cadherin, decreased N-Cadherin).

Conclusion: Erianin induces Ferroptosis via PDP2-mediated activation of the JNK signaling pathway, thereby restraining ovarian Cancer growth in vitro and in vivo. These findings provide a mechanistic rationale for further evaluation of Erianin as a ferroptosis-inducing therapeutic candidate, including in chemoresistant settings.

Erianin; Ferroptosis; JNK signaling pathway; Ovarian cancer; PDP2.