Interplay between ferroptosis and cuproptosis in chronic kidney disease: Mechanisms and regulatory crosstalk.

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.

Key Findings

• Ferroptosis and cuproptosis are metal-dependent regulated cell death pathways implicated in chronic kidney disease (CKD) pathogenesis.
• These pathways are interconnected through shared mechanisms such as redox imbalance, mitochondrial dysfunction, and disrupted metal homeostasis.
• The regulatory nodes including the GSH-GPX4 axis, p53, and Nrf2 integrate antioxidant defense, metal metabolism, and mitochondrial function, linking ferroptosis and cuproptosis in CKD.

Clinical Significance

Citation

Hu Qiongshi, Yang Lina. Interplay between ferroptosis and cuproptosis in chronic kidney disease: Mechanisms and regulatory crosstalk. Biochimica et biophysica acta. Molecular basis of disease. 2026-Oct-02.