Abstract
Primary Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia and bleeding tendency. Exosomes mediate abnormal crosstalk between immune cells and megakaryocytes in ITP, suggesting that exosome-related genes may serve as potential candidates for understanding disease pathogenesis. ITP transcriptome data and exosome-related genes (ERGs) were retrieved from public databases. Potential candidate genes were preliminarily identified by intersecting ITP’s differentially expressed genes (DEGs) with exosome-related key module genes, followed by exploratory screening via machine learning and the construction of a preliminary predictive model. Multi-dimensional analyses (enrichment, immune infiltration [subsequently removed due to methodological concerns], drug prediction) and RT-qPCR validation were performed. Four candidate genes (GABARAPL1, SLC39A14, HIBADH, GSR) were identified through bioinformatic analysis, involved in spliceosome and other pathways (P < 0.05, |NES| > 1). GABARAPL1, SLC39A14, and HIBADH showed exploratory correlations with specific functional T-cell subsets (|cor| > 0.3, P < 0.05). Molecular docking simulations suggested potential binding feasibility between SLC39A14/nortriptyline and GSR/oxiglutatione (binding free energy < -5 kcal/mol). RT-qPCR confirmed the significant downregulation of GABARAPL1, SLC39A14, and GSR in ITP patients (P < 0.05), while HIBADH did not show statistically significant changes (P > 0.05). In this exploratory study, GABARAPL1, SLC39A14, and GSR were identified as potential candidate biomarkers with experimental support from clinical samples. HIBADH, while predicted by bioinformatic analysis, requires further investigation to determine its clinical relevance. These findings provide exploratory insights and a preliminary basis for future hypothesis-driven research on the role of exosome-related genes in ITP.
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Data availability
The dataset (GSE43179) supporting the conclusions of this article is available in the [GEO] repository, [https://www.ncbi.nlm.nih.gov/geo/]. The ERGs data are available in the [ExoBCD] repository, [https://exobcd.liumwei.org/].Source of the validation set: GEO database (https://www.ncbi.nlm.nih.gov/geo), with the accession number GSE205495.
References
Schramm, T. et al. Fibrinolysis is impaired in patients with primary immune thrombocytopenia. J. Thromb. Haemost. 22 (11), 3209–3220 (2024).
Cao, J. et al. MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages. Cell. Mol. Immunol. 20 (12), 1413–1427 (2023).
Schifferli, A. et al. Adolescents and young adults with newly diagnosed primary immune thrombocytopenia. Haematologica 108 (10), 2783–2793 (2023). Published 2023 Oct 1.
Author, R. M. et al. Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15–18 March 2016. Crit Care. ;20:347. Published 2016 Oct 24. (2016).
Hu, Y. et al. Efficacy and safety of sovleplenib (HMPL–523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM–01): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Haematol. 11 (8), e567–e579 (2024).
Zhuang, X. et al. Decreased cyclooxygenase–2 associated with impaired megakaryopoiesis and thrombopoiesis in primary immune thrombocytopenia. J. Transl Med. 21 (1), 540 (2023). Published 2023 Aug 12.
Huang, Y. et al. Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21 + Regulatory T Cell-Mediated Immune Suppression via MiR–363–3p. Inflamm. Published online March 4, (2025).
Larue, M. et al. Efficacy and safety of dapsone in adult primary immune thrombocytopenia. Blood Adv. 9 (8), 1976–1983 (2025).
Yan, S. et al. A phase 2 trial of orelabrutinib showing promising efficacy and safety in patients with persistent or chronic primary immune thrombocytopenia. Am. J. Hematol. 99 (7), 1392–1395 (2024).
Goodman, S. R. The exosome collection. Cell. Mol. Biol. Lett. 30 (1), 33 (2025). Published 2025 Mar 24.
Arya, S. B., Collie, S. P. & Parent, C. A. The ins-and-outs of exosome biogenesis, secretion, and internalization. Trends Cell. Biol. 34 (2), 90–108 (2024).
Isaac, R., Reis, F. C. G., Ying, W. & Olefsky, J. M. Exosomes as mediators of intercellular crosstalk in metabolism. Cell. Metab. 33 (9), 1744–1762 (2021).
Fang, Y. et al. Exosomes as biomarkers and therapeutic delivery for autoimmune diseases: Opportunities and challenges. Autoimmun. Rev. 22 (3), 103260 (2023).
Shen, Z. et al. Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases. Front. Immunol. 12, 749192 (2021). Published 2021 Sep 27.
Huang, Y. et al. Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21 + Regulatory T Cell-Mediated Immune Suppression via MiR–363–3p. Inflamm. Published online March 4, (2025).
Sun, Y. et al. Proteomic analysis and microRNA expression profiling of plasma-derived exosomes in primary immune thrombocytopenia. Br. J. Haematol. 194 (6), 1045–1052 (2021).
Wang, J., Qing, M., Gui, J., Zhong, P. & Hua, H. Identification of exosome-related genes associated with prognosis and immune infiltration features in pancreatic cancer. Discov Oncol. 16 (1), 192 (2025). Published 2025 Feb 17.
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43 (7), e47 (2015).
Shi, Y. et al. Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy. Apoptosis 28 (9–10), 1423–1435 (2023).
Gustavsson, E. K., Zhang, D., Reynolds, R. H., Garcia-Ruiz, S. & Ryten, M. ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2. Bioinformatics 38 (15), 3844–3846 (2022).
Horvath, S. & Dong, J. Geometric interpretation of gene coexpression network analysis. PLoS Comput. Biol. 4 (8), e1000117 (2008). Published 2008 Aug 15.
Wu, T. et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov. (Camb). 2 (3), 100141 (2021). Published 2021 Jul 1.
Kanehisa, M. et al. KEGG: biological systems database as a model of the real world. Nucleic Acids Res. 53 (D1), D672–D677 (2025).
Kanehisa, M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 28 (11), 1947–1951 (2019).
Kanehisa, M. & Goto, S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28 (1), 27–30 (2000).
Smoot, M. E., Ono, K., Ruscheinski, J., Wang, P. L. & Ideker, T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27 (3), 431–432 (2011).
Mahmoudian, M., Venäläinen, M. S., Klén, R. & Elo, L. L. Stable Iterative Variable Selection Bioinf. ;37(24):4810–4817. (2021).
Friedman, J., Hastie, T. & Tibshirani, R. Regularization Paths for Generalized Linear Models via Coordinate Descent. J. Stat. Softw. 33 (1), 1–22 (2010).
Li, M. et al. Recognition of refractory Mycoplasma pneumoniae pneumonia among Myocoplasma pneumoniae pneumonia in hospitalized children: development and validation of a predictive nomogram model. BMC Pulm Med. 23 (1), 383 (2023). Published 2023 Oct 10.
Robin, X. et al. pROC: an open-source package for R and S + to analyze and compare ROC curves. BMC Bioinform. 12, 77 (2011). Published 2011 Mar 17.
Nazari-Ghadikolaei, A., Fikse, F., Gelinder Viklund, Å. & Eriksson, S. Factor analysis of evaluated and linearly scored traits in Swedish Warmblood horses. J. Anim. Breed. Genet. 140 (4), 366–375 (2023).
Wu, T. et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov. (Camb). 2 (3), 100141 (2021). Published 2021 Jul 1.
Qi, W. Y. et al. Immune cells in metabolic associated fatty liver disease: Global trends and hotspots (2004–2024). World J. Hepatol. 17 (3), 103327 (2025).
González-López, T. J. & Provan, D. The new era of primary immune thrombocytopenia management in adults: A narrative review of current and emerging treatments. Blood Rev. 73, 101300 (2025).
Li, G. et al. The therapeutic potential of exosomes in immunotherapy. Front. Immunol. 15, 1424081 (2024). Published 2024 Jul 8.
Guo, H. et al. Dysfunction of astrocytic glycophagy exacerbates reperfusion injury in ischemic stroke. Redox Biol. 74, 103234 (2024).
Li, L. et al. Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis. Bone Res. 13 (1), 32 (2025). Published 2025 Mar 3.
Panahi Meymandi, A. R. et al. Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications. Front. Immunol. 14, 1212695 (2023). Published 2023 Aug 22.
Yan, J. et al. Platelet Pharmacytes for the Hierarchical Amplification of Antitumor Immunity in Response to Self-Generated Immune Signals. Adv. Mater. 34 (23), e2109517 (2022).
Mo, J. et al. Comprehensive analysis and prediction model of mitophagy and ferroptosis in primary immune thrombocytopenia. Br. J. Haematol. 204 (6), 2429–2441 (2024).
Yang, Y. et al. SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma. Cell. Rep. Med. 6 (9), 102300 (2025).
Shao, Y. et al. SLC39A10 is a key zinc transporter in T cells and its loss mitigates autoimmune disease. Sci. China Life Sci. 68 (7), 1855–1870 (2025).
Deng, Z. et al. Mesenchymal Stem Cells Prevent SLC39A14-Dependent Hepatocyte Ferroptosis through Exosomal miR–16–5p in Liver Graft. Adv. Sci. (Weinh). 12 (6), e2411380 (2025).
Sauer, A. K. et al. Zinc is a key regulator of gastrointestinal development, microbiota composition and inflammation with relevance for autism spectrum disorders. Cell. Mol. Life Sci. 79 (1), 46 (2021). Published 2021 Dec 22.
Ma, L. et al. lncRNA, miRNA, and mRNA of plasma and tumor-derived exosomes of cardiac myxoma-related ischaemic stroke. Sci Data. ;12(1):91. Published 2025 Jan 16. (2025).
Tukacs, V. et al. Chronic Cerebral Hypoperfusion-Induced Disturbed Proteostasis of Mitochondria and MAM Is Reflected in the CSF of Rats by Proteomic Analysis. Mol. Neurobiol. 60 (6), 3158–3174 (2023).
Chen, W. et al. Mitochondrial enzyme HIBADH protects against calcium oxalate nephrolithiasis by modulating oxidative stress and apoptosis. Arch. Biochem. Biophys. 770, 110452 (2025).
Bishop, C. A. et al. Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle. Nutr. Diabetes. 12 (1), 20 (2022). Published 2022 Apr 13.
Huang, Y. et al. Plasma Exosomes Derived from Patients with Primary Immune Thrombocytopenia Attenuate TBX21 + Regulatory T Cell-Mediated Immune Suppression via MiR–363–3p. Inflamm. Published online March 4, (2025).
Zhang, R. et al. Pleiotropic effects of a mitochondrion-targeted glutathione reductase inhibitor on restraining tumor cells. Eur. J. Med. Chem. 248, 115069 (2023).
Zhan, Y. et al. Impaired mitochondria of Tregs decreases OXPHOS-derived ATP in primary immune thrombocytopenia with positive plasma pathogens detected by metagenomic sequencing. Exp. Hematol. Oncol. 11 (1), 48 (2022). Published 2022 Sep 1.
Xie, Y. et al. PM2.5 promotes platelet activation and thrombosis via ROS/MAPKs pathway-mediated mitochondrial dysfunction. Environ. Res. 283, 122116 (2025).
Wang, C., Xu, M., Fan, Q., Li, C. & Zhou, X. Therapeutic potential of exosome-based personalized delivery platform in chronic inflammatory diseases. Asian J. Pharm. Sci. 18 (1), 100772 (2023).
Wang, J. et al. Second-generation antipsychotics induce cardiotoxicity by disrupting spliceosome signaling: Implications from proteomic and transcriptomic analyses. Pharmacol. Res. 170, 105714 (2021).
Sun, T. et al. Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia. Br. J. Haematol. 204 (6), 2418–2428 (2024).
Karginov, T. A., Ménoret, A. & Vella, A. T. Optimal CD8 + T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape. Nat. Commun. 13 (1), 3540 (2022). Published 2022 Jun 20.
Pellagatti, A. et al. Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations. Blood 132 (12), 1225–1240 (2018).
Zhao, Z. et al. Targeted delivery of exosomal miR–484 reprograms tumor vasculature for chemotherapy sensitization. Cancer Lett. 530, 45–58 (2022).
Li, H. et al. Mir–484 contributes to diminished ovarian reserve by regulating granulosa cell function via YAP1-mediated mitochondrial function and apoptosis. Int. J. Biol. Sci. 18 (3), 1008–1021 (2022). Published 2022 Jan 1.
Lin, T. et al. Identification of exosomal miR–484 role in reprogramming mitochondrial metabolism in pancreatic cancer through Wnt/MAPK axis control. Pharmacol. Res. 197, 106980 (2023).
Guo, Y. et al. Rbms1 promotes pulmonary fibrosis by stabilising Sumo2 mRNA to facilitate Smad4-SUMOylation and fibroblast activation. Eur. Respir J. 66 (3), 2401667 (2025). Published 2025 Sep 25.
De Luca, B. et al. Efficacy and tolerability of antidepressants in individuals suffering from physical conditions and depressive disorders: network meta-analysis. Br. J. Psychiatry. 227 (2), 553–566 (2025).
Acknowledgements
The authors gratefully acknowledge the technical support and facilities provided by the Department of Hematology at the First Affiliated Hospital of Chongqing Medical University and Fengdu County Traditional Chinese Medicine Hospital.
Funding
This study was supported by grants from the Chongqing Medical Scientific Research Project (Grant No. 2025MSXM065) and the Chongqing Natural Science Foundation (Grant No. CSTB2025NSCQ-GPX1218).
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F.F.L.completed the bioinformatics analysis component of this study, drafted the initial manuscript, and participated in subsequent revisions. Z.Y.C.and Z.H.Y.systematically organized the research data and refined all figures and tables. J.Y.S.and J.P.collected clinical specimens and performed analytical processing of the research outco mes. P.H.and Z.S.Y.were responsible for the conceptual framework and methodological rigor of this study, additionally conducting critical reviews of the revised manuscript for academic coherence.
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Lou, F., Chen, Z., Yuan, Z. et al. Exploring exosome-related genes as candidate biomarkers in primary immune thrombocytopenia through transcriptomics and preliminary experimental validation. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43618-1
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DOI: https://doi.org/10.1038/s41598-026-43618-1
