Preclinical models of Wilson's disease: From pathogenesis to clinical translation

Wilson's disease (WD) is an autosomal recessive disorder of copper homeostasis caused by pathogenic ATP7B variants, leading predominantly to hepatic and neurological injury. Extensive heterogeneity in genotype, age at onset, clinical presentation, and treatment response complicates both diagnosis and therapeutic development, highlighting the need for reliable experimental models that reproduce distinct features of WD pathogenesis. This review critically evaluates animal models, conventional cell systems, induced pluripotent stem cell models, and organoids of WD, with an emphasis on the phenotypes reproduced, experimental strengths and limitations, and translational applications of each platform. Rodent models have been instrumental in defining mechanisms of hepatic copper accumulation and toxicity and remain widely used for preclinical therapeutic evaluation, but existing models do not adequately reproduce the neurological manifestations characteristic of human WD. Patient-derived cells and organoids provide complementary platforms for investigating mutation-specific pathobiology, individualized drug responses, and genome-editing strategies, although incomplete maturation, limited cellular complexity, and insufficient standardization remain important constraints. Future progress will depend on models that more faithfully capture neurological disease, greater use of humanized systems, improved physiological fidelity of organoids, and standardized criteria for phenotypic assessment. Integrating complementary models across the preclinical pipeline should strengthen mechanistic insight and accelerate development of precision therapies for WD.