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<p>Ovarian cancer remains the most lethal gynecologic malignancy, with acquired platinum resistance accounting for the majority of treatment failures. 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—iron-abundant ascites, the lipid-rich omental niche, and prevalent BRCA mutations—present distinctive therapeutic opportunities. We introduce the novel concepts of a “ferroptosis compensatory threshold” 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.</p>

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Ferroptosis and chemotherapy resistance in ovarian cancer: molecular mechanisms and therapeutic opportunities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Shuqing Li,
  • Lina Yang,
  • Zhiling Zhu

摘要

Ovarian cancer remains the most lethal gynecologic malignancy, with acquired platinum resistance accounting for the majority of treatment failures. 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—iron-abundant ascites, the lipid-rich omental niche, and prevalent BRCA mutations—present distinctive therapeutic opportunities. We introduce the novel concepts of a “ferroptosis compensatory threshold” 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.