Preclinical Models of Wilson’s Disease: From Pathogenesis Elucidation to Clinical Translation

Wilson’s disease (WD) is an autosomal recessive copper metabolism disorder caused by ATP7B mutations, leading to multi-organ damage. Clinical heterogeneity poses diagnostic challenges and current treatments fail to cure it. Preclinical models are vital for bridging basic research and clinical translation. This review systematically summarizes key WD models: animal models (rodents, large mammals, gene-edited models) for in vivo mechanistic studies and therapeutic validation, cell-based models for cellular mechanism exploration, iPSC models for personalized research, and organoid models for 3D tissue simulation, and conducts a comparative analysis of the advantages, limitations and translational applicability of different models. These models facilitate pathogenesis elucidation, novel drug development and gene therapy validation with the latest research progress. However, existing models lack adequate neurological symptom simulation and standardization, and almost all preclinical models except LEC rats fail to recapitulate WD-related cholangiocarcinoma and sporadic hepatocellular carcinoma complications. Future directions include optimizing humanized models, upgrading organoid systems, establishing standardization, developing novel large animal models, and integrating multi-model strategies for precision translational research. This review provides a reference for selecting appropriate models to advance WD precision medicine.