Copper-induced suppression of the PPARα-FABP1 axis sensitizes hepatocytes to ferroptosis in Wilson disease.

Abstract

Wilson disease (WD) is characterized by hepatic copper accumulation and progressive liver injury, yet the mechanisms linking copper overload to hepatocellular damage remain incompletely understood. Here, we identify suppression of the PPARα-FABP1 axis as a key metabolic vulnerability that sensitizes hepatocytes to ferroptosis in WD. Liver tissues from WD patients and Atp7b^⁻/⁻ mice exhibited impaired antioxidant capacity, enhanced lipid peroxidation, and coordinated downregulation of PPARα-FABP1 signaling at both transcriptomic and proteomic levels. In hepatocytes, copper exposure increased nuclear-enriched copper and caused a time-dependent repression of PPARα and FABP1, lowered the threshold for RSL3-induced ferroptotic cell death, and enhanced lipid peroxidation. These effects were mimicked by silencing either PPARα or FABP1 and were partially rescued by ferroptosis inhibition. Integration of published lipidomic datasets revealed accumulation of peroxidized polyunsaturated fatty acids in WD, while FABP1 overexpression mitigated arachidonic acid-driven lipid peroxidation and ferroptosis. Clinically, hepatic expression and circulating levels of FABP1 declined with disease severity and were associated with inflammatory activity and fibrosis stage in WD patients, showing moderate predictive value for adverse outcomes. Together, these findings establish copper-induced suppression of the PPARα-FABP1 axis as a mechanistic link between metabolic dysregulation and ferroptosis in WD, highlighting a potential therapeutic vulnerability in copper-associated liver disease.