铁、铜死亡机制在胶质瘤治疗中的应用与展望

Application and prospects of ferroptosis and cuproptosis mechanisms in treatment of glioma

摘要:

胶质瘤是中枢神经系统中最常见的原发性恶性肿瘤。铁死亡和铜死亡是细胞异常代谢所引发的2种细胞死亡机制，铁死亡通过脂质过氧化和氧化应激引发细胞死亡，而铜死亡则通过破坏线粒体代谢功能引发细胞死亡，两者均在胶质瘤的发生、发展及治疗中展现出重要作用。近年来的研究表明，通过调控谷胱甘肽过氧化物酶4（GPX4）通路可以靶向铁死亡来有效杀伤胶质瘤细胞，而通过调控二氢硫辛酰胺乙酰转移酶（DLAT）通路则可以靶向铜死亡来有效杀伤胶质瘤细胞，两种方法均可以克服部分传统治疗的耐药性。两者在代谢网络和肿瘤免疫微环境（TIME）中存在交叉并共同影响肿瘤进展，所以联合诱导铁死亡与铜死亡展现出协同增效的抗肿瘤前景。尽管相关的机制研究成果和纳米技术为临床应用提供了新策略，但生物毒性和血脑屏障的存在使纳米技术药物递送系统的临床转化面临挑战。系统梳理和总结该领域的研究进展，对推动科学研究和促进纳米技术药物递送系统改进具有重要意义。该文旨在综述近年来与铁死亡和铜死亡相关的分子机制以及两者在胶质瘤治疗中的应用，探讨相关基因作为诊断与预后标志物的临床应用价值，分析当前面临的主要挑战，展望未来发展方向。

Abstract:

Glioma is the most common primary malignant tumor in the central nervous system. Ferroptosis and cuproptosis are two novel forms of cell death mechanisms triggered by dysregulated iron and copper metabolism， and ferroptosis induces cell death through lipid peroxidation and oxidative stress， whereas cuproptosis causes cell death by disrupting mitochondrial metabolic functions. Both ferroptosis and cuproptosis play an important role in the development， progression， and treatment of glioma. Recent studies have shown that targeting ferroptosis by modulating pathways such as glutathione peroxidase 4 （GPX4） can effectively kill glioma cells， while targeting cuproptosis by regulating dihydrolipoyl acetyltransferase （DLAT） and related pathways can also achieve efficient elimination of glioma cells； both methods can overcome drug resistance associated with certain traditional therapies. These two mechanisms interact with each other in metabolic networks and tumor immune microenvironment and mutually affect tumor progression， and therefore， combined induction of ferroptosis and cuproptosis has shown a synergistic antitumor potential. Although related mechanistic research and nanotechnology have provided new strategies for clinical application， there are still challenges in the bench-to-bedside translation of nanotechnology-based drug delivery systems due to the presence of biotoxicity and blood-brain barrier. A systematic review of the research advances in this field is of great importance for promoting scientific research and improving nanotechnology-based drug delivery systems. This article reviews the recent advances in the molecular mechanisms of ferroptosis and cuproptosis， explores their application in the treatment of glioma， discusses the clinical application value of related genes as markers for diagnosis and prognosis， analyzes the current main challenges， and proposes future research directions.