铜死亡在卵巢癌中的作用机制及治疗新进展

The Mechanism of Cuproptosis in Ovarian Cancer and New Advances in Its Treatment

摘要: 卵巢癌病死率位居妇科恶性肿瘤首位，约70%患者确诊时已处于晚期，5年生存率长期徘徊在30%~40%。铜死亡作为一种新型程序性细胞死亡方式，其核心机制在于过量铜离子诱导的蛋白毒性应激。研究表明，卵巢癌组织中铜离子浓度显著升高，铜死亡相关基因(Cuproptosis-Related Genes, CRGs)表达谱发生明显改变，且与患者预后、铂类药物耐药及肿瘤微环境重塑密切相关。基于CRGs的表达特征与生物学功能，可将卵巢癌铜死亡调控网络归纳为三大功能模块：铜死亡敏感性决定因子(FDX1、LIAS等)下调介导肿瘤细胞产生“铜死亡抵抗”；铜稳态与药物外排调控因子(CTR1、ATP7A/B)构成连接铜死亡–铂耐药的关键共同靶点；能量代谢核心枢纽(DLD、DLAT等)高表达提示肿瘤高度依赖线粒体呼吸，进而形成代谢脆弱性。CRGs与微环境双向调控：缺氧抑制铜死亡，铜死亡激活抗肿瘤免疫；驱动基因突变中，p53突变削弱铜死亡响应，BRCA突变为协同PARP抑制剂提供依据。靶向铜死亡的干预策略主要包括铜离子载体、谷胱甘肽耗竭剂、纳米递送系统等，与传统治疗联用可发挥协同抗肿瘤效应。本文系统梳理铜死亡在卵巢癌中的调控网络，提出CRGs功能模块划分理论，以期为卵巢癌的精准治疗提供理论依据与新靶点。

Abstract: The case fatality rate of ovarian cancer ranks first among gynecological malignancies, with approximately 70% of patients diagnosed at an advanced stage, and the 5-year survival rate has long hovered between 30% and 40%. Cuproptosis, as a novel form of programmed cell death, is fundamentally characterized by protein toxic stress induced by excessive copper ions. Studies have shown that copper ion concentrations are significantly elevated in ovarian cancer tissues, and the expression profiles of Cuproptosis-Related Genes (CRGs) are markedly altered, closely associated with patient prognosis, platinum-based drug resistance, and tumor microenvironment remodeling. Based on the expression characteristics and biological functions of CRGs, the regulatory network of cuproptosis in ovarian cancer can be summarized into three functional modules: downregulation of cuproptosis sensitivity determinants (such as FDX1, LIAS) mediates the development of “cuproptosis resistance” in tumor cells; regulators of copper homeostasis and drug efflux (such as CTR1, ATP7A/B) constitute key common targets connecting cuproptosis and platinum resistance; and high expression of core energy metabolism hubs (such as DLD, DLAT) indicates a high dependence of tumors on mitochondrial respiration, thereby creating metabolic vulnerabilities. The bidirectional regulation between CRGs and the tumor microenvironment is characterized by hypoxia inhibiting cuproptosis, while cuproptosis activates anti-tumor immunity. Among driver gene mutations, p53 mutation attenuates cuproptosis response, and BRCA mutation provides a rationale for synergizing with PARP inhibitors. Intervention strategies targeting cuproptosis mainly include copper ionophores, glutathione depletors, and nano-delivery systems, which can exert synergistic anti-tumor effects when combined with conventional therapies. This article systematically reviews the regulatory network of cuproptosis in ovarian cancer and proposes a functional module classification theory for CRGs, aiming to provide a theoretical basis and new targets for precision therapy in ovarian cancer.