Ferroptosis Signature Correlates with Ovarian Cancer Prognosis and Chemotherapy Response.

BACKGROUND: Ovarian cancer is a leading cause of gynecological cancer mortality, with late diagnosis, high recurrence and chemotherapy resistance closely linked to the tumor microenvironment (TME). Ferroptosis, an iron-dependent regulated cell death, is a promising therapeutic target, but its role in ovarian cancer TME remodeling and treatment resistance remains unclear.

METHODS: We integrated bulk transcriptome and single-cell multi-omics datasets from ovarian cancer patient cohorts. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were applied to develop and externally validate a ferroptosis-related risk signature (FRS) across independent cohorts including TCGA-OV and GSE14764. We systematically analyzed correlations between FRS and clinical outcomes, TME immune landscape, somatic genomic aberrations, as well as computationally predicted chemotherapeutic susceptibility. Subsequent in vitro assays using two ovarian cancer cell lines (SKOV3 and Caov-3) were conducted to preliminarily explore the combined anti-tumor activity of Erastin and paclitaxel, alongside underlying molecular associations.

RESULTS: We established a 17‑gene‑based Ferroptosis Sensitivity Score (FRS), with a mean index of 0.741 across the cohort. FRS effectively stratified patients into high/low-risk groups with significant survival differences; high-risk patients had a suppressive immune TME, enriched tumor-promoting pathways and distinct genomic alterations. FRS was an independent prognostic biomarker, and a nomogram integrating FRS and clinical features improved survival prediction. In vitro, Erastin dose-dependently upregulated ferroptosis-associated proteins in SKOV3 and Caov-3 cells; combining Erastin with paclitaxel alleviated paclitaxel resistance, induced apoptosis, and transcriptomic analysis showed DEGs enriched in cell division, cell cycle, MAPK and lipid metabolism pathways, confirming their synergistic anti-tumor effect via regulating ferroptosis, apoptosis and multiple signaling pathways.

CONCLUSION: This work constructs a ferroptosis-derived risk signature with prognostic and chemoresponse predictive value for ovarian cancer, supported by multi-omics cohort analysis. Preliminary in vitro data from two ovarian cancer cell lines (SKOV3 and Caov-3) imply combinatorial Erastin-paclitaxel treatment may exert synergistic anti-tumor effects and alleviate paclitaxel resistance. Our findings offer preliminary clues correlating ferroptosis with TME remodeling and lay a preliminary theoretical foundation for exploring combinatorial regimens to counter chemoresistance in ovarian cancer.