Disrupted copper homeostasis promotes osteopontin-mediated hepatocyte–stellate cell crosstalk in Wilson disease

Abstract

Wilson disease is a prototypical disorder of copper metabolism in which hepatic copper overload drives progressive liver injury and fibrosis, yet the molecular mechanisms linking copper accumulation to fibrogenesis remain poorly defined. Here, we identify osteopontin (OPN) as a copper-responsive hepatokine that mechanistically couples copper overload to hepatic stellate cell activation. Using ATP7B-deficient models, we show that hepatic copper accumulation is accompanied by liver injury, inflammatory infiltration, and fibrotic remodeling, together with marked induction of OPN. In hepatocytes, copper exposure led to intracellular copper accumulation and oxidative stress, resulting in robust upregulation and secretion of OPN, which was partially attenuated by antioxidant treatment. Conditioned medium from copper-stressed hepatocytes promoted stellate cell activation and extracellular matrix deposition, whereas genetic depletion of SPP1 in hepatocytes markedly blunted these pro-fibrotic effects, establishing OPN as a key paracrine mediator of copper-induced hepatocyte–stellate cell crosstalk. Clinically, hepatic and circulating OPN levels were significantly elevated in patients with Wilson disease and closely associated with copper burden, fibrosis severity, and liver stiffness. Moreover, serum OPN independently predicted histological fibrosis with good diagnostic performance. Collectively, these findings reveal a copper-driven secretory pathway that links disrupted copper homeostasis to liver fibrogenesis and highlight OPN as a metal-responsive mediator and potential biomarker in Wilson disease.