{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:02:38Z","timestamp":1785420158474,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170798"],"award-info":[{"award-number":["82170798"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82170798"],"award-info":[{"award-number":["82170798"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brainstem malignancy for which effective treatment options are lacking. Cerebrospinal fluid (CSF) analysis can reveal intrinsic alterations and characteristic metabolic profiles of the tumor microenvironment. In this study, the proteome and metabolome of CSF from DIPG patients were comprehensively analyzed to identify potential biomarkers and the pathways involved. Functional annotation and pathway enrichment analyses were performed using the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. Bioinformatics methods were used to comprehensively analyze the proteomic and metabolomic results to identify key differentially expressed proteins, metabolites, and potential signaling pathways involved in DIPG. In total, 885 DEPs (differentially expressed proteins) were identified in cerebrospinal fluid from DIPG patients, of which 54 were upregulated and 831 were downregulated, primarily originating from the cytoplasm and cell membrane. Among the top 20 upregulated proteins, URB1 (nucleolar pre-ribosomal-associated protein 1) had the greatest statistical significance, while the remaining proteins were mostly immunoglobulin fragments. GO enrichment analysis revealed that the downregulated proteins were enriched primarily in cellular processes, metabolic processes, and binding functions. KEGG analysis revealed that upregulated proteins were significantly enriched in complement and coagulation cascades, whereas downregulated proteins were primarily associated with endocytosis and certain microbial infections. A total of 1372 metabolites were identified, of which 40 were differentially expressed: 24 were upregulated, and 16 were downregulated. Pathway analyses of the differentially expressed metabolites revealed that they were primarily related to purine metabolism and tyrosine metabolism. The multiomics analysis revealed that purine metabolism is particularly important in DIPG.<\/jats:p>","DOI":"10.3390\/ijms27156688","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:54:26Z","timestamp":1785153266000},"page":"6688","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Proteomic and Metabolomic Analyses of Cerebrospinal Fluid from Pediatric Patients with Diffuse Intrinsic Pontine Glioma"],"prefix":"10.3390","volume":"27","author":[{"given":"Yufan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunkun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8759-7636","authenticated-orcid":false,"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Institute for Pediatric Research, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/neuonc\/nox021","article-title":"Diffuse intrinsic pontine gliomas-current management and new biologic insights. Is there a glimmer of hope?","volume":"19","author":"Cohen","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_2","first-page":"1","article-title":"Declines in Cancer Death Rates Among Youth: United States, 2001\u20132021","volume":"484","author":"Curtin","year":"2023","journal-title":"NCHS Data Brief."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ccell.2018.11.015","article-title":"Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression","volume":"35","author":"Larson","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1093\/neuonc\/nox107","article-title":"Contemporary survival endpoints: An International Diffuse Intrinsic Pontine Glioma Registry study","volume":"19","author":"Cooney","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nm.3855","article-title":"Functionally defined therapeutic targets in diffuse intrinsic pontine glioma","volume":"21","author":"Grasso","year":"2015","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/nan.12553","article-title":"Review: Peering through a keyhole: Liquid biopsy in primary and metastatic central nervous system tumours","volume":"45","author":"Bertero","year":"2019","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s11060-014-1432-3","article-title":"Proteomic analyses of CSF aimed at biomarker development for pediatric brain tumors","volume":"118","author":"Samuel","year":"2014","journal-title":"J. Neuro-Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41586-019-0882-3","article-title":"Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid","volume":"565","author":"Miller","year":"2019","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"vdaf270","DOI":"10.1093\/noajnl\/vdaf270","article-title":"Targeted next-generation sequencing-based sequencing of cell-free DNA in cerebrospinal fluid uncovers cancer-specific mutations in patients with brain cancer using a widely available panel","volume":"8","author":"Westarp","year":"2026","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/j.ccell.2021.09.012","article-title":"Serial assessment of measurable residual disease in medulloblastoma liquid biopsies","volume":"39","author":"Liu","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/neuonc\/nos067","article-title":"Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid","volume":"14","author":"Saratsis","year":"2012","journal-title":"Neuro-Oncology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"188721","DOI":"10.1016\/j.bbcan.2022.188721","article-title":"Proteomics and metabolomics approach in adult and pediatric glioma diagnostics","volume":"1877","author":"Pienkowski","year":"2022","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1007\/s00415-019-09665-7","article-title":"Cerebrospinal fluid-based metabolomics to characterize different types of brain tumors","volume":"267","author":"Wang","year":"2020","journal-title":"J. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1038\/s41598-020-80647-w","article-title":"Potential biomarkers of childhood brain tumor identified by proteomics of cerebrospinal fluid from extraventricular drainage (EVD)","volume":"11","author":"Bruschi","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ghantasala, S., Pai, M.G.J., Biswas, D., Gahoi, N., Mukherjee, S., Kp, M., Nissa, M.U., Srivastava, A., Epari, S., and Shetty, P. (2021). Multiple Reaction Monitoring-Based Targeted Assays for the Validation of Protein Biomarkers in Brain Tumors. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.548243"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1002\/ijc.24639","article-title":"Elevated levels of MIC-1\/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome","volume":"125","author":"Shnaper","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1743-8454-5-1","article-title":"Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas","volume":"5","author":"Wong","year":"2008","journal-title":"Cerebrospinal Fluid Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2290790","DOI":"10.1080\/2162402X.2023.2290790","article-title":"Cerebrospinal fluid immunological cytokines predict intracranial tumor response to immunotherapy in non-small cell lung cancer patients with brain metastases","volume":"13","author":"Li","year":"2023","journal-title":"Oncoimmunology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1158\/1078-0432.CCR-19-2840","article-title":"Proteomic Analysis of CSF from Patients with Leptomeningeal Melanoma Metastases Identifies Signatures Associated with Disease Progression and Therapeutic Resistance","volume":"26","author":"Smalley","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1074\/jbc.273.2.814","article-title":"Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral","volume":"273","author":"Ikeda","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41401-022-00961-z","article-title":"Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression","volume":"44","author":"He","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000239795","article-title":"TMEM25, REPS2 and Meis 1: Favourable prognostic and predictive biomarkers for breast cancer","volume":"30","author":"Doolan","year":"2009","journal-title":"Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1007\/s12094-018-02029-z","article-title":"Identification a novel set of 6 differential expressed genes in prostate cancer that can potentially predict biochemical recurrence after curative surgery","volume":"21","author":"Li","year":"2019","journal-title":"Clin. Transl. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.7314\/APJCP.2013.14.5.2851","article-title":"Expression and clinical significance of REPS2 in human esophageal squamous cell carcinoma","volume":"14","author":"Zhang","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s11060-016-2236-4","article-title":"RalA is overactivated in medulloblastoma","volume":"130","author":"Ginn","year":"2016","journal-title":"J. Neuro-Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2306359","DOI":"10.1002\/advs.202306359","article-title":"JPT2 Affects Trophoblast Functions and Macrophage Polarization and Metabolism, and Acts as a Potential Therapeutic Target for Recurrent Spontaneous Abortion","volume":"11","author":"Chen","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106888","DOI":"10.1016\/j.micpath.2024.106888","article-title":"Dysbiosis of the gut microbiota in glioblastoma patients and potential biomarkers for risk assessment","volume":"195","author":"Jiang","year":"2024","journal-title":"Microb. Pathog."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s12088-021-00962-2","article-title":"Alterations of the Gut Microbiome in Recurrent Malignant Gliomas Patients Received Bevacizumab and Temozolomide Combination Treatment and Temozolomide Monotherapy","volume":"62","author":"Zhu","year":"2022","journal-title":"Indian J. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1126\/science.aay9189","article-title":"The human tumor microbiome is composed of tumor type-specific intracellular bacteria","volume":"368","author":"Nejman","year":"2020","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e0045724","DOI":"10.1128\/msystems.00457-24","article-title":"Multi-omics analysis reveals the interplay between intratumoral bacteria and glioma","volume":"10","author":"Li","year":"2025","journal-title":"mSystems"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liang, J., Li, T., Zhao, J., Wang, C., and Sun, H. (2022). Current understanding of the human microbiome in glioma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.781741"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S125","DOI":"10.1093\/neuonc\/noad181","article-title":"Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from PNOC","volume":"26","author":"Mueller","year":"2024","journal-title":"Neuro-Oncology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"M111.014688","DOI":"10.1074\/mcp.M111.014688","article-title":"Metabolomics of human cerebrospinal fluid identifies signatures of malignant glioma","volume":"11","author":"Locasale","year":"2012","journal-title":"Mol. Cell. Proteom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40478-024-01722-1","article-title":"The genomic alterations in glioblastoma influence the levels of CSF metabolites","volume":"12","author":"Wang","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s40478-018-0588-z","article-title":"Analysis of cerebrospinal fluid metabolites in patients with primary or metastatic central nervous system tumors","volume":"6","author":"Ballester","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s13167-020-00211-4","article-title":"Comparative cerebrospinal fluid metabolites profiling in glioma patients to predict malignant transformation and leptomeningeal metastasis with a potential for preventive personalized medicine","volume":"11","author":"Im","year":"2020","journal-title":"EPMA J."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zeiner, P.S., Kinzig, M., Div\u00e9, I., Maurer, G.D., Filipski, K., Harter, P.N., Senft, C., B\u00e4hr, O., Hattingen, E., and Steinbach, J.P. (2019). Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients. J. Clin. Med., 8.","DOI":"10.3390\/jcm8122031"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1016\/j.cell.2024.05.011","article-title":"De novo and salvage purine synthesis pathways across tissues and tumors","volume":"187","author":"Tran","year":"2024","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, S., Zhang, S., Wang, Z., Li, J., Yuan, Y., Li, T., Zuo, M., Feng, W., Li, W., and Chen, M. (2022). Purine metabolism-related gene expression signature predicts survival outcome and indicates immune microenvironment profile of gliomas. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1038272"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3811","DOI":"10.1038\/s41467-020-17512-x","article-title":"Purine metabolism regulates DNA repair and therapy resistance in glioblastoma","volume":"11","author":"Zhou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s40170-024-00341-7","article-title":"Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma","volume":"12","author":"Peterson","year":"2024","journal-title":"Cancer Metab."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6688\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:55:13Z","timestamp":1785153313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":42,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156688"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156688","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}