{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:55:29Z","timestamp":1790596529731,"version":"4.1.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in ATP7B, with the liver being one of the earliest and most prominently affected organs. ATP7B dysfunction impairs copper incorporation into ceruloplasmin and biliary copper excretion, resulting in progressive hepatic copper accumulation and a cascade of pathological responses, including proteostasis disturbance, mitochondrial dysfunction, oxidative stress, metabolic remodeling, inflammation, and fibrogenesis. Given the dynamic progression of WD-associated liver injury from early copper dysregulation to chronic hepatitis, fibrosis, cirrhosis, and acute liver failure-like decompensation, appropriate experimental model selection is essential for mechanistic studies and therapeutic development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a structured narrative review of\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      models of WD-associated hepatic injury, with searches updated through August 2026, and evaluated each model according to genetic fidelity, disease-stage representation, dominant mechanism, tissue complexity, and translational objective. We then developed a stage-, mechanism-, and objective-oriented model-selection framework.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Different WD models recapitulate distinct stages and features of hepatic injury. Severe Atp7b-deficient rat models, including the LEC rat, are particularly suitable for investigating severe liver injury, mitochondrial copper toxicity, and rapid decoppering interventions. tx-j mice and early-stage Atp7b\u2212\/\u2212 mice effectively model early hepatic copper accumulation, metabolic remodeling, and epigenetic alterations. Atp7b\u2212\/\u2212 mice, tx mice, LEC survivors, and Labrador retriever copper-associated hepatitis models are valuable for studying chronic copper hepatopathy, inflammation, and fibrosis. Variant-specific models are most informative for defining mutation-level defects in ATP7B folding, trafficking, stability, or transport and for testing mutation-compatible interventions; they should not be interpreted as establishing deterministic clinical genotype\u2013phenotype relationships. Direct ATP7B-deficient models and copper-overload reference models are treated as distinct experimental categories throughout this Review. For fibrosis research, simple copper-exposed hepatocyte or hepatic stellate cell systems are insufficient to reproduce disease complexity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>No single experimental model adequately captures the full spectrum of WD-associated hepatic injury. Model selection should be guided by the experimental question across disease stage, mechanistic hypothesis, genetic fidelity, tissue complexity, and translational objective. The most robust strategy is a tiered model-selection and validation pipeline in which genetic fidelity, tissue complexity, and therapeutic endpoint are increased as a finding moves from mechanistic discovery toward preclinical translation. WD-specific multicellular organoid and liver-on-chip systems remain a major unmet methodological need.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1930939","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:01:02Z","timestamp":1790593262000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Experimental models of hepatic injury in Wilson disease: stage-specific mechanisms and translational applications"],"prefix":"10.3389","volume":"17","author":[{"given":"Ting","family":"Cheng","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Chinese Medicine","place":["Hefei, China"]},{"name":"Brain Disease Research Institute, Anhui University of Chinese Medicine","place":["Hefei, 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