铁死亡与铜死亡在慢性肾脏病中的相互作用：机制与调控串扰
Interplay between ferroptosis and cuproptosis in chronic kidney disease: Mechanisms and regulatory crosstalk.
摘要(中文译文)
慢性肾脏病（CKD）以肾脏结构和功能的进行性、不可逆性恶化为特征，构成重大的全球公共卫生负担。铁死亡和铜死亡是近年来发现的两种金属依赖性调节性细胞死亡形式，均与CKD的发病机制相关。重要的是，这两条通路并非独立运作，而是通过涉及氧化还原失衡、线粒体功能障碍和金属稳态紊乱的共同机制发生汇聚。CKD相关微环境包括代谢功能障碍、尿毒症毒素蓄积、慢性缺氧、炎症和细胞外基质重塑，可增强肾细胞对上述两种过程的易感性。共同的调控节点，尤其是GSH-GPX4轴、p53和Nrf2，整合了抗氧化防御、金属代谢和线粒体功能，从而将这两条通路联系起来。在本综述中，我们系统总结了铁死亡和铜死亡在CKD中的分子机制，讨论了CKD微环境如何重塑细胞对铁死亡和铜死亡的易感性，并重点阐述了GSH-GPX4轴、p53和Nrf2作为潜在分子汇聚枢纽的调控作用。我们还探讨了尚未解决的关键问题，包括两者相互作用的直接证据有限、对细胞类型特异性机制的理解不完整、缺乏可靠的生物标志物以及临床转化面临的挑战。总体而言，现有证据支持以下观点：铁死亡和铜死亡是金属-氧化还原-线粒体网络中依赖情境且相互关联的组成部分，对其精准调控可能为CKD提供基于机制、由生物标志物指导的新型干预策略。
Abstract
Chronic kidney disease (CKD) is characterized by progressive and irreversible deterioration of renal structure and function, posing a substantial global public health burden. Ferroptosis and cuproptosis are two recently identified forms of metal-dependent regulated cell death implicated in CKD pathogenesis. Importantly, these pathways do not operate independently; rather, they converge through shared mechanisms involving redox imbalance, mitochondrial dysfunction, and disrupted metal homeostasis. The CKD-associated microenvironment, encompassing metabolic dysfunction, uremic toxin accumulation, chronic hypoxia, inflammation, and extracellular matrix remodeling, enhances renal cell susceptibility to both processes. Common regulatory nodes, particularly the GSH-GPX4 axis, p53, and Nrf2, integrate antioxidant defense, metal metabolism, and mitochondrial function, thereby linking these two pathways. In this review, we systematically summarize the molecular mechanisms of ferroptosis and cuproptosis in CKD, discuss how the CKD microenvironment reshapes cellular susceptibility to ferroptosis and cuproptosis, and highlight the regulatory roles of the GSH-GPX4 axis, p53, and Nrf2 as potential molecular convergence hubs. We also address key unresolved issues, including limited direct evidence for their interaction, incomplete understanding of cell type-specific mechanisms, the lack of reliable biomarkers, and challenges in clinical translation. Collectively, current evidence supports the concept that ferroptosis and cuproptosis are context-dependent and interconnected components of a metal-redox-mitochondrial network, and that its precise modulation may offer novel strategies for mechanism-based, biomarker-guided intervention in CKD.
如何引用
AMA
Qiongshi Hu, Lina Yang. Interplay between ferroptosis and cuproptosis in chronic kidney disease: Mechanisms and regulatory crosstalk.. Biochimica et biophysica acta. Molecular basis of disease. 2026; doi:10.1016/j.bbadis.2026.168489.
APA
Qiongshi Hu, Lina Yang (2026). Interplay between ferroptosis and cuproptosis in chronic kidney disease: Mechanisms and regulatory crosstalk.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168489
GB/T 7714
Qiongshi Hu, Lina Yang. Interplay between ferroptosis and cuproptosis in chronic kidney disease: Mechanisms and regulatory crosstalk.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2026 doi:10.1016/j.bbadis.2026.168489.
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