Petriaggi Lavinia, Giorgio Emanuele, Natali Giuseppe, Galeano Cristiana, Furtado Simão Rodrigues, Faniello Concetta Maria, Costanzo Francesco Saverio, Biamonte Flavia, Battaglia Anna Martina
Department of Clinical and Experimental Medicine, "Magna Graecia" University of Catanzaro, 88100 Catanzaro, Italy.
Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal.
Front Biosci (Landmark Ed). 2025 Jul 24;30(7):39675. doi: 10.31083/FBL39675.
Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy characterized by frequent late-stage diagnosis, high rates of chemoresistance, and poor long-term survival. Emerging evidence underscores the central role of iron metabolism dysregulation in EOC pathogenesis, progression, and treatment resistance. Ovarian cancer cells and cancer stem cells exhibit an "iron-addicted" phenotype, characterized by increased iron uptake, reduced export, and enhanced storage, which sustains proliferative signaling, redox imbalance, and metastatic potential. Recent advances have illuminated ferroptosis, a regulated form of iron-dependent cell death driven by lipid peroxidation, as a promising therapeutic target for overcoming resistance to platinum-based chemotherapy. This review provides a comprehensive synthesis of the mechanisms governing iron metabolism and ferroptosis in EOC, with a particular focus on Class IV ferroptosis inducers (FINs). These agents act by disrupting iron homeostasis and promoting labile iron pool accumulation, thereby triggering oxidative stress and ferroptotic death. Preclinical studies demonstrate that Class IV FINs, including iron nitroprusside, superparamagnetic iron oxide nanoparticles, ferric ammonium citrate, and Ferlixit, exhibit potent antitumor activity in EOC models, particularly in chemoresistant and stem-like tumor subpopulations. Furthermore, Class IV FINs show synergistic effects when combined with other ferroptosis modulators or immunotherapeutic agents. Despite their promise, clinical translation remains limited by challenges in bioavailability, delivery specificity, and potential systemic toxicity. Ongoing efforts in nanotechnology, biomarker discovery, and tumor stratification offer new avenues for refining ferroptosis-based interventions. Ultimately, this review highlights Class IV FINs as a mechanistically distinct and clinically actionable strategy to target metabolic vulnerabilities in EOC, with the potential to reshape therapeutic paradigms and improve patient outcomes.
上皮性卵巢癌（EOC）是一种极具致死性的妇科恶性肿瘤，其特征为晚期诊断频繁、化疗耐药率高且长期生存率低。新出现的证据强调了铁代谢失调在EOC发病机制、进展和治疗耐药中的核心作用。卵巢癌细胞和癌症干细胞表现出一种“铁成瘾”表型，其特征是铁摄取增加、输出减少和储存增强，这维持了增殖信号、氧化还原失衡和转移潜能。最近的进展揭示了铁死亡，一种由脂质过氧化驱动的铁依赖性细胞死亡的调节形式，作为克服铂类化疗耐药的有前景的治疗靶点。本综述全面综合了EOC中铁代谢和铁死亡的调控机制，特别关注IV类铁死亡诱导剂（FINs）。这些药物通过破坏铁稳态和促进不稳定铁池积累起作用，从而引发氧化应激和铁死亡。临床前研究表明，包括硝普铁、超顺磁性氧化铁纳米颗粒、柠檬酸铁铵和Ferlixit在内的IV类FINs在EOC模型中表现出强大的抗肿瘤活性，特别是在化疗耐药和干细胞样肿瘤亚群中。此外，IV类FINs与其他铁死亡调节剂或免疫治疗药物联合使用时显示出协同作用。尽管它们前景广阔，但临床转化仍受到生物利用度、递送特异性和潜在全身毒性等挑战的限制。纳米技术、生物标志物发现和肿瘤分层方面的持续努力为优化基于铁死亡的干预措施提供了新途径。最终，本综述强调IV类FINs是一种机制独特且具有临床可操作性的策略，可针对EOC中的代谢脆弱性，有可能重塑治疗模式并改善患者预后。
