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

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. This study was supported by the Regional Innovation and Development Joint Fund of NSFC (U22A20366, 82505546) and the Anhui Province Traditional Chinese Medicine Science and Technology Research Special Project (202303a07020004). It also received support from the Anhui Province Clinical Medical Research and Translation Special Project (No. 202204295107020066) and the Anhui Provincial Natural Science Foundation (2408085QH283).

Additional support came from the Anhui Provincial Higher Education Research Project (2024AH051003), Anhui University of Traditional Chinese Medicine Clinical Research Project (2024YFYLCZX17), and Anhui Provincial Department of Education Scientific Research Project (2025AHGXZK40547). These authors contributed equally: Nannan Qian, Hu Xi. Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China Nannan Qian, Hu Xi, Yuqi Song, Jun Li, Yulong Yang, Zhihong Rao, Shu Zhai, Wei He, Gaoyuan Qin, Ting Cheng & Wenming Yang Graduate School, Anhui University of Chinese Medicine, Hefei, China Nannan Qian, Yuqi Song, Yulong Yang, Zhihong Rao, Wei He, Gaoyuan Qin & Wenming Yang Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China Key Laboratory of Xin’An Medicine, Ministry of Education, Hefei, China Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China Correspondence to Nannan Qian, Ting Cheng or Wenming Yang.