Copper dyshomeostasis, mitochondrial dysfunction, and regulated cell death in Wilson disease

Abstract

Abstract Wilson disease (WD) results from ATP7B dysfunction, yet genotype and total copper burden do not fully account for variation across organs, patients, and disease stages. Growing interest in cuproptosis and ferroptosis has exposed a central interpretive problem: mitochondrial injury, pathway-associated markers, and execution of a specific death program are not equivalent. We integrate copper trafficking, mitochondrial biology, and regulated cell death (RCD) using three evidence levels: human WD observations, WD-model evidence, and non-WD extrapolation. Across the literature, mitochondrial copper loading and structural, bioenergetic, redox, and quality-control abnormalities have stronger support than canonical execution of any individual RCD pathway. Cuproptosis-consistent changes remain incomplete and predominantly preclinical. Ferroptosis-like injury, apoptosis, CASP9–CASP3–gasdermin E (GSDME)-dependent lytic cell death, and necroptosis-related signaling have unequal, largely model-based support. We therefore treat them as parallel, context-dependent modules rather than a dominant pathway or fixed sequence. This distinction also clarifies organ specificity. Hepatic injury is best characterized, whereas neurological WD requires consideration of central nervous system barriers, regional copper and iron handling, white-matter injury, and glial responses. Applying the same evidence criteria separates established copper-related tests and treatments from exploratory mitochondrial or RCD biomarkers and modulators. RCD-directed interventions remain a research agenda, and current copper-directed care is unchanged. The field must now determine whether, when, and where individual RCD pathways contribute to WD, and under which conditions. Resolving this question will require time-resolved, organ-specific studies that combine pathway-specific execution criteria, functional perturbation or rescue, and longitudinal clinical outcomes.

The authors' abstract, as published at the source. Cell Death Discovery, 2026 · DOI ↗