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Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a metabolic vulnerability that therapy-resistant cancers cannot fully evade. This review examines the relationship between ferroptosis and chemotherapy resistance in high-grade serous ovarian cancer (HGSOC), analyzing the GPX4 antioxidant axis, polyunsaturated fatty acid biosynthesis, and iron homeostasis. We highlight recent discoveries including BRCA1-dependent ubiquitination of GPX4 and its implications for PARP inhibitor synthetic lethality, NR1D2-mediated transcriptional repression of FSP1, and stromal protection conferred by cancer-associated fibroblasts. The unique features of ovarian cancer\u2014iron-abundant ascites, the lipid-rich omental niche, and prevalent BRCA mutations\u2014present distinctive therapeutic opportunities. We introduce the novel concepts of a \u201cferroptosis compensatory threshold\u201d requiring concurrent multi-node inhibition, and the need for personalized therapeutic design based on tumor ferroptosis defense profiling. We also address challenges confronting clinical translation: on-target toxicities, resistance mechanisms, spatial heterogeneity in ferroptosis susceptibility, and the need for validated predictive biomarkers. By synthesizing these cutting-edge findings, we provide a framework that integrates cancer genetics, microenvironment metabolism, and immunology, distinguishing this review from previous summaries and highlighting actionable vulnerabilities for overcoming chemoresistance in ovarian cancer.<\/jats:p>","DOI":"10.1186\/s13048-026-02150-6","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:25:16Z","timestamp":1780410316000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ferroptosis and chemotherapy resistance in ovarian cancer: molecular mechanisms and therapeutic opportunities"],"prefix":"10.1186","volume":"19","author":[{"given":"Shuqing","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiling","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"issue":"3","key":"2150_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, et al. 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