Uncovering the Critical Role of Cuproptosis in Wilson Disease: Insights Into Potential Therapeutic Targets

ABSTRACT Wilson disease (WD) is an inherited disorder caused by ATP7B mutations, resulting in toxic copper accumulation primarily in the liver and brain. While copper‐induced hepatotoxicity is a hallmark of WD, the mechanisms linking copper overload to liver injury remain unclear. This study aimed to investigate the role of cuproptosis, a copper‐dependent form of regulated cell death, in WD pathogenesis and identify key cuproptosis‐related genes (CRGs). We utilised ATP7B−/− mice and HepG2 cells to model WD. Liver injury was assessed histologically and biochemically. Transcriptomic analysis identified differentially expressed CRGs, followed by machine learning (LASSO, SVM‐RFE) to identify key genes. Functional enrichment and protein validation were performed. Candidate biomarkers were evaluated in WD patient serum and confirmed in the mouse model. ATP7B−/− mice showed marked hepatocellular injury with elevated AST, ALT and LDH. Cuproptosis markers (FDX1, DLST, DLAT, LIAS) were upregulated in both liver tissue and HepG2 cells. Copper exposure decreased cell viability and increased LDH release, exacerbated by Elesclomol and alleviated by Tetrathiomolybdate. Transcriptomics revealed Lox, App, Afp, Alb, Gpc1, Gls were central hub genes. Importantly, SiRNA knockdown of Gpc1, Gls, Lox and App alleviated cuproptosis, supporting their key roles in cuproptosis. Cuproptosis plays a critical role in copper‐induced liver injury in WD. Key mediators identified include Gpc1, Gls, Lox and App, which were validated as potential therapeutic targets. These findings provide new insights into the molecular mechanisms underlying WD and may inform the development of targeted treatment strategies.