ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1635137
Integrated Proteomics and Single-Cell Transcriptomics Reveal Potential Therapeutic Targets in Wilson’s Disease Patients
Provisionally accepted
- The First Hospital of Jilin University, Changchun, China
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Purpose: Wilson’s Disease (WD), an autosomal recessive ATP7B mutations disorder causing copper accumulation, poses diagnostic challenges. This study used proteomics and single-cell transcriptomics to identify WD mechanisms and therapeutic targets. Methods: Proteomic analysis was conducted on clinical samples from WD patients and the control group, followed by validation via ELISA. Subsequently, an integrated analysis was conducted by combining these data with single-cell RNA sequencing data from the database. Analytical content included differential expression, functional enrichment, drug target prediction, immune infiltration, and subtype-specific biomarker screening via LASSO/SVM-REF. Results: Proteomic analysis identified 420 differentially expressed proteins (266 upregulated, 154 downregulated) in WD patients compared with healthy controls, with significant enrichment in inflammatory pathways. Integration with DrugBank revealed eight hub proteins with high diagnostic accuracy (AUC > 0.9), among which Inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) and Transthyretin (TTR) may regulate the PI3K-Akt signaling pathway. Subsequently, ELISA validation confirmed significantly reduced levels of TTR, Ceruloplasmin (CP), and ITIH1 proteins in WD. Considering the heterogeneity of the WD microenvironment and single-cell diversity, further single-cell transcriptomic analysis was performed. The results revealed immune dysregulation, characterized by increased macrophage infiltration and reduced T/NK cell proportions, and PI3K-Akt-mTOR pathway enrichment in macrophages. For subtype-specific analysis, six key proteins were identified to distinguish hepatic and brain subtypes (AUC > 0.9). Conclusions: The hub proteins and subtype-specific biomarkers identified in this study provide potential targets for the precise treatment of WD, while emphasizing the critical role of the PI3K-Akt pathway in WD.
Keywords: Wilson's Disease, Proteomics, Single-cell transcriptomics, ITIH1, TTRImmune Microenvironment, PI3K-Akt pathway
Received: 26 May 2025; Accepted: 29 Aug 2025.
Copyright: © 2025 Sun, Qi, Xu, Zhou, Yuan, Yu, Cao and Hua. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rui Hua, The First Hospital of Jilin University, Changchun, China
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