The pathogenesis of liver fibrosis in Wilson's disease: hepatocyte injury and regulation mediated by copper metabolism dysregulation.

Wilson's disease (WD) is a rare autosomal recessive disorder caused by mutations in ATP7B, which is marked by defective copper metabolism that leads to toxic copper buildup in organs such as the liver and brain, ultimately causing hepatocellular injury and liver fibrosis. This review systematically examined the multifaceted mechanisms through which copper overload drives liver fibrosis. In short, copper ions generate reactive oxygen species via the Fenton reaction, thereby directly impairing the mitochondrial structure and function and inducing hepatocyte apoptosis, necrosis, and cuproptosis. Copper ions also activate signaling pathways such as the TGF-β1/Smad and NF-κB pathways, which stimulate hepatic stellate cells and promote their transdifferentiation into collagen-secreting myofibroblasts, which then accelerate extracellular matrix deposition. Moreover, abnormal lipoylation of the copper-dependent proteins metal-binding domain of ferredoxin 1 and dihydrolipoamide transacetylase causes mitochondrial protein oligomer buildup and tricarboxylic acid cycle dysfunction, reinforcing an "oxidative damage-inflammation-fibrosis" vicious cycle. The disruption of copper chaperones and lysosomal copper accumulation further intensifies oxidative stress and dysregulates the immune microenvironment. Current therapies focus mainly on copper chelation but exhibit limited ability to reverse established fibrosis. Meanwhile, emerging gene therapies face the challenges of delivery efficiency and immunogenicity. Future research should therefore elucidate the dynamic interplay between copper metabolism and the liver microenvironment, identify key regulatory nodes across different disease stages, and shift treatment paradigms from narrow "symptomatic copper chelation" to integrated strategies aimed at restoring copper homeostasis. Such advances could yield novel approaches toward the prevention and treatment of WD liver fibrosis.