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Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson’s disease (WD), Menkes disease (MD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber–Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

Copper (Cu) is a vitally important micronutrient, whose balance between essential and toxic levels requires a tightly regulated network of proteins. Dysfunction in key components of this network leads to the disruption of Cu homeostasis, resulting in fatal disorders such as Wilson disease, which is caused by mutations in the hepatic Cu efflux transporter ATP7B. Unfortunately, the molecular targets for normalizing Cu homeostasis in Wilson disease remain poorly understood. Here, using genome-wide screening, we identified the cellular prion protein (PrP) as an important mediator of Cu toxicity in WD. Loss of ATP7B stimulates hepatic expression of PrP, which promotes endocytic Cu uptake, leading to toxic Cu overload. Suppression of PrP significantly reduces Cu toxicity in cell and animal models of Wilson disease. These findings highlight the critical regulatory role of PrP in copper metabolism and open new avenues for exploring the therapeutic potential of PrP suppression in Wilson disease. This study reveals that prion protein (PrP) promotes copper toxicity in Wilson disease by facilitating copper endocytosis. The authors demonstrate that suppressing PrP reduces copper overload and liver damage, offering a potential therapeutic strategy for this fatal inherited disorder.

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.

Cuproptosis, a newly characterized form of regulated cell death driven by copper accumulation, has emerged as a significant mechanism underlying various non-cancerous diseases. This review delves into the complex interplay between copper metabolism and the pathogenesis of conditions such as Wilson’s disease (WD), neurodegenerative disorders, and cardiovascular pathologies. We examine the molecular mechanisms by which copper dysregulation induces cuproptosis, highlighting the pivotal roles of key copper transporters and enzymes. Additionally, we evaluate the therapeutic potential of copper chelation strategies, which have shown promise in experimental models by mitigating copper-induced cellular damage and restoring physiological homeostasis. Through a comprehensive synthesis of recent advancements and current knowledge, this review underscores the necessity of further research to translate these findings into clinical applications. The ultimate goal is to harness the therapeutic potential of targeting cuproptosis, thereby improving disease management and patient outcomes in non-cancerous conditions associated with copper dysregulation.

Hepatolenticular degeneration (HLD), also known as Wilson's disease (WD), is a rare autosomal recessive disorder regarding copper metabolism. Whether gut microbiota imbalance is involved in developing HLD remains unknown. A comprehensive 16S rRNA amplicon sequencing, metagenomic sequencing, and metabonomic analysis were undertaken in patients with WD to analyze the composition and function profiles of gut microbiota in patients with WD. The data demonstrated differences in gut microbiota and metabolic pathways between WD patients and normal individuals, significantly decreasing bacterial richness and diversity. The levels of Selenomonaceae and Megamonas in WD patients are significantly higher than those in healthy individuals. The relative abundances of Roseburia inulinivorans in patients with WD are lower than in healthy individuals. Compared with healthy people, the level of metabolites in patients with WD is abnormal. Leucylproline, 5-Phenylvaleric Acid and N-Desmethylclobazam, which have nutritional and protective effects, are significantly reduced fecal metabolites in patients with WD. D-Gluconic acid, which can chelate metal ions, may be a potential treatment for WD. The positive correlation it demonstrates with Alistipes indistinctus and Prevotella stercora indicates potential bacteria able to treat WD. These metabolites are mainly related to the biosynthesis of antibiotics, alpha-linolenic acid metabolism, one carbon pool by folate, nicotinate and nicotinamide metabolism. In conclusion, the data from this study elucidate novel mechanisms describing how abnormal gut miccrobiota contribute to the pathogenesis of WD and outlines new molecules for the treatment of WD.

Copper, an indispensable trace element in living organisms, plays a pivotal role in human physiological processes. Wilson's disease (WD), an inherited disorder of copper metabolism, is caused by mutations in the ATP7B gene. This genetic malfunction disrupts the dynamics of copper transport and metabolism, thereby impairing ceruloplasmin synthesis and copper excretion. The resultant accumulation of copper in various tissues and organs precipitates a cascade of cellular demise and functional impairment. Notably, cuproptosis, a recently discovered copper-dependent regulated cell death mechanism, distinctly deviates from conventional cell death paradigms. This novel mode of cell death involves the interaction of copper with lipoacylated proteins within the tricarboxylic acid cycle, leading to proteinotoxic stress and culminating in cell death. In the realm of pathophysiology, cuproptosis has emerged as a pivotal player in a spectrum of diseases, with WD standing as a paradigm closely intertwined with the dysregulation of copper metabolism. This study aimed to encapsulate the pivotal molecular underpinnings of cuproptosis and delve into its crucial involvement in the etiopathogenesis of WD. By elucidating these mechanisms, the present analysis contributes significantly to the nuanced understanding of the pathological underpinnings of WD, thereby providing fresh insights and evidence that may direct innovative therapeutic strategies for this condition.

Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b −/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b −/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b −/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b −/− mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b −/− mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b −/− mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b −/− mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b −/− mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b −/− mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b −/− mice.

There is accumulating evidence that ceruloplasmin, a copper protein with ferroxidase activity, plays an important role in iron metabolism. The genetic disorder, aceruloplasminemia, can lead to tissue storage of iron as in hemochromatosis. Because most patients with Wilson's disease, a genetic copper toxicosis, have hypoceruloplasminemia, some could be affected by iron overload. Four male patients with Wilson's disease were enrolled in this study of pre- and post-treatment iron metabolism. Pretreatment copper contents of the liver were high in all four male patients studied as diagnostic of Wilson's disease. Genetic analysis supported their clinical diagnosis of Wilson's disease without a background of hemochromatosis. Pretreatment serum ceruloplasmin levels were <20 mg/dl in all four patients. A standard penicillamine treatment for 3–8.5 yr further decreased their serum ceruloplasmin levels. Post-treatment serum ferroxidase activity was low as was the serum ceruloplasmin protein. Copper contents in the liver decreased after treatment in all subjects. In contrast, nonheme iron in the liver increased during treatment. Pretreatment liver specimens were positive for histochemical iron in two patients, and post-treatment specimens were positive in all four patients. In two patients, serum aminotransferase levels rebounded with elevation of serum ferritin concentration during the treatment period. Subsequent iron reduction by phlebotomy ameliorated their biochemical liver damage. Iron overload related to hypoceruloplasminemia may be clinically important, particularly in male patients with Wilson's disease.

Novel therapies for Wilson disease (WD) will require appropriate biomarkers and clinically relevant endpoints to demonstrate therapeutic efficacy. We aimed to develop robust, minimally invasive biomarker assays to assess target engagement in future clinical trials for WD therapeutics. We conducted a single-center, sample collection biomarker study in 21 patients with WD and 6 control participants. Serum, liver fine needle aspiration biopsy (FNA), and liver core needle biopsy (CNB) samples were collected from participants. RNA and protein were isolated from serum exosome and biopsy samples. Samples were analyzed for mRNA expression by quantitative PCR and for protein expression by a novel electrochemiluminescence (ECL) immunoassay. ATP7B mRNA was detectable in FNA, CNB, and serum exosome samples. However, serum exosomes are not yet a viable method for ATP7B quantification. ATP7B protein was only detectable in CNB samples. We compared the FNA and CNB results for five WD patients and found mRNA expression levels to be comparable with an R 2 of 0.64 with statistical significance. The methods we developed may be useful in clinical settings to quantify hepatocyte-specific expression of ATP7B for the development of novel therapeutics for Wilson disease.