2026-08-17 | A Dual-Function Guanidinium Scaffold for Copper sequestration and Redox Protection in Wilson disease Models.
Wilson disease (WD) is caused due to mutations in the copper ATPase gene ATP7B, resulting in accumulation of copper and the consequent disruption of cellular redox balance through reactive oxygen species generation. Current therapies mainly depend on copper chelation to lower metal burden which sometimes also strip copper from cuproproteins and disturb key physiological copper-dependent processes. It also does not directly suppress pathological copper reactivity i.e., free radical generation, a major driver of WD progression. To overcome these limitations, we have rationally designed Gua-Cu-3, a C3-symmetric guanidinium-based non-toxic molecule that can chelate labile copper without metal stripping from cuproproteins due to moderate binding affinity and it has intrinsic antioxidant activity within a single nanosheet-forming supramolecular self-assembly. Spectroscopic, calorimetric, and computational analyses revealed multivalent copper coordination (Kd = 95.4μM) while radical-scavenging and hydroxyl-radical inhibition assays revealed redox-regulatory activity. In copper loaded hepatocytes, Gua-Cu-3 reduces ATP7B trafficking from trans-Golgi network, confirming effective intracellular copper sequestration. This was accompanied by a marked reduction in oxidative stress readouts, i.e., translocation of Nrf2 in nucleus and of HO-1 expression, thereby limiting lipid peroxidation and restoration of ER and mitochondrial health. Gua-Cu-3 attenuates oxidative stress in ATP7B-homolog-deficient Caenorhabditis elegans and rescues copper-induced developmental defects in zebrafish, outperforming D-penicillamine, which is currently in use for WD management. These findings establish Gua-Cu-3 with a therapeutic potential that couples-controlled copper sequestration with redox regulation and provides a framework for treating WD and other disorders associated with metal dyshomeostasis and oxidative stress.
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2026-08-15 | Recent advances in research on high-frequency mutations in the ATP7B gene associated with Wilson disease in the Chinese population: from genetic evolution to precision medicine.
Wilson disease (WD) is a hereditary disorder of copper metabolism caused by mutations in the ATP7B gene; the Chinese population exhibits a unique, high-frequency mutation profile centered on the R778L and P992L mutations. This article provides a narrative review of the genetic evolution, molecular pathogenic mechanisms, phenotypic heterogeneity, and precision diagnosis and treatment strategies for high-frequency ATP7B mutations in the Chinese WD population. The high-frequency enrichment of R778L and P992L is speculated to arise from the combined effects of CpG mutation hotspots and the founder effect supported by East Asian haplotype data, with distinct geographical distributions and relatively conserved haplotypes observed in existing cohorts. Functional studies indicate that the R778L variant disrupts the transmembrane domain and induces severe protein misfolding associated with an early-onset hepatic phenotype, whereas the P992L mutation partially retains catalytic function and tends to present neurological manifestations in many clinical cohorts, though individual phenotypic variation remains substantial. Preclinical molecular chaperone and gene editing strategies offer potential mechanistic targets for mutation-specific intervention, yet their clinical translation remains at an immature stage with insufficient human trial data. In the future, it will be necessary to establish multicenter cohorts, advance mutation-targeted therapies, and develop a precision diagnosis and treatment system covering the entire disease lifecycle.
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2026-08-14 | Liver Organoids: From Disease Modelling to Regenerative Medicine.
Liver organoids are three-dimensional miniature liver models that recapitulate the complex architecture and key functions of the human liver in vitro, offering powerful platforms for both fundamental research and translational applications. This review systematically summarises current fabrication strategies, disease-modelling utilities and regenerative potentials of liver organoids, alongside the major challenges and future directions. In recent years, the field has witnessed several breakthroughs. Through endothelial co-culture approaches, vascularised and metabolically zonated liver organoids have been successfully generated, achieving endothelial coverage exceeding 85%. Prime editing enables precise correction of pathogenic mutations in patient-derived organoids, with no off-target effects detected at the genome-wide level. In disease modelling, iPSC-derived liver organoids faithfully recapitulate the pathological progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and verify the lipid-lowering efficacy of semaglutide. Macrophage-integrated organoid models support the full life cycles of HEV, SARS-CoV-2 and dengue virus, providing new tools for antiviral drug screening. Large-scale patient-derived tumour organoid biobanks successfully preserve the heterogeneity and clinical drug-resistance signatures of liver cancers. In regenerative medicine, encapsulated hepatocyte organoids and the UTOpiA bioartificial liver system have effectively rescued acute liver failure in animal models, while gene-edited autologous organoids offer potential curative strategies for genetic disorders such as Wilson disease. Nevertheless, insufficient hepatocyte functional maturity, difficulties in constructing vascular networks, and the lack of standardised culture protocols remain major obstacles to clinical translation. By bridging fundamental liver biology and clinical practice, liver organoid technology lays a solid foundation for precision hepatology and regenerative therapies. Continued interdisciplinary efforts are still required to overcome current limitations and facilitate its clinical adoption.
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2026-08-09 | Copper homeostasis and cuproptosis: New perspectives on the diagnosis and treatment of metabolic diseases.
Cuproptosis is a recently identified form of regulated cell death driven by the direct binding of Cu⁺ to the lipoyl moiety of mitochondrial tricarboxylic acid (TCA) cycle enzymes, leading to dihydrolipoamide S-acetyltransferase (DLAT) oligomerisation, iron-sulfur cluster (Fe-S) protein depletion, and proteotoxic stress, and is uniquely dependent on mitochondrial respiration. This review critically synthesises current evidence on the role of cuproptosis in type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and obesity. In T2DM, three causally validated pathways of copper transporter dysregulation converge on ferredoxin 1 (FDX1)-dependent DLAT oligomerisation, with substantial FDX1 reduction in diabetic skeletal muscle providing quantitative evidence of cuproptotic commitment; however, β-cell-specific knockout studies remain critically absent. In MASLD, indirect reactive oxygen species (ROS)-mediated insulin resistance is favoured over direct copper-receptor interactions. We propose the metabolic threshold hypothesis, positing that cuproptosis represents failed adaptation to chronic lipid overload, triggered when copper influx exceeds the combined buffering capacity of ATPase copper transporting beta (ATP7B)-mediated efflux, metallothionein sequestration, and glutathione (GSH) chelation. The serum Cu/Zn ratio cannot distinguish cuproptosis from ferroptosis; precise identification requires combined detection of FDX1, DLAT, lipoic acid synthase (LIAS), and lipoyltransferase 1 (LIPT1) with mitochondrial copper content, with immunohistochemistry (IHC) for DLAT oligomerisation as the most clinically accessible surrogate marker. Copper chelators including tetrathiomolybdate and merestinib are primary agents for metabolic tissue preservation, whereas ionophores such as elesclomol are restricted to oncology, with lipid nanoparticle-based delivery platforms essential to overcome the blood-brain barrier challenge, as underscored by the neurological worsening documented in D-penicillamine-treated Wilson disease patients. The interplay between cuproptosis and ferroptosis, sharing GSH depletion but diverging at lipoylated protein aggregation versus glutathione peroxidase 4 (GPX4)-dependent lipid peroxidation, suggests dual-pathway inhibition may be necessary. Future priorities include validation of the metabolic threshold hypothesis, β-cell-specific knockout studies, standardised DLAT oligomerisation diagnostics, tissue-targeted copper modulator delivery, and integration of cuproptosis biomarkers with multi-omics and artificial intelligence for clinically stratified precision medicine.
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2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
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