{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:36:28Z","timestamp":1785436588413,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"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":["82404681"],"award-info":[{"award-number":["82404681"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62371293"],"award-info":[{"award-number":["62371293"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62231025"],"award-info":[{"award-number":["62231025"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82404681"],"award-info":[{"award-number":["82404681"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["62371293"],"award-info":[{"award-number":["62371293"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["62231025"],"award-info":[{"award-number":["62231025"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Lactylation, a recently identified post-translational modification, has been associated with multiple cancer types, including neuroblastoma (NB). The present study aimed to investigate the prognostic significance of lactylation-related genes and to develop a prognostic model to enhance patient risk stratification and guide targeted therapy for NB. In the present bioinformatics study, single-cell RNA sequencing data (GSE137804) were analyzed to quantify lactylation activity in NB cells using the AddModuleScore algorithm based on 371 lactylation-related genes. A total of 142 differentially expressed lactylation-related genes (DELGs) were identified between high- and low-lactylation tumor cells, and these genes were mainly enriched in cell cycle-related pathways. A 14-gene lactylation-related prognostic model was then constructed using the identified DELGs in a training cohort (GSE49710, n = 349) via Cox and LASSO regression, and validated in internal (GSE49710, n = 149) and external (E-MTAB-8248, n = 223) cohorts. The model effectively stratified patients into high- and low-risk groups with significantly different overall survival (OS) outcomes, and its robust predictive performance was confirmed across both validation cohorts. The present study reveals the significant prognostic role of lactylation in NB, and the 14-gene model serves as a novel molecular tool for risk stratification and provides a reference for developing targeted therapeutic strategies for NB.<\/jats:p>","DOI":"10.3390\/molecules31132280","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T15:27:37Z","timestamp":1782746857000},"page":"2280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell RNA Sequencing Reveals Lactylation Modifications in Neuroblastoma and the Construction of a Prognostic Model"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1877-0001","authenticated-orcid":false,"given":"Wuhe","family":"Jike","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8815-8138","authenticated-orcid":false,"given":"Junming","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9212-6999","authenticated-orcid":false,"given":"Kutluk","family":"Kasim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6527-7551","authenticated-orcid":false,"given":"Xiao","family":"Zhi","sequence":"additional","affiliation":[{"name":"School of Medicine, Shanghai Jiao Tong University, No. 800 Dong Chuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lufeng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"},{"name":"Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"},{"name":"Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"},{"name":"Institute of Materia Medica, Xinjiang Medical University, No. 567 Shangde North Road, Shuimogou District, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","unstructured":"Pediatric Oncology Committee, Chinese Anti-Cancer Association, and Oncology Group, Chinese Association of Pediatric Surgeons (2022). Expert consensus on diagnosing and treating of neuroblastoma in children: CCCG-NB-2021 Regimen. Chin. J. Pediatr. Surg., 43, 588\u2013598."},{"key":"ref_2","first-page":"448","article-title":"Research frontiers and reflections on neuroblastoma","volume":"50","author":"Pu","year":"2023","journal-title":"Chin. J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1056\/NEJMra0804577","article-title":"Recent Advances in Neuroblastoma","volume":"362","author":"Maris","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41571-022-00643-z","article-title":"Advancing Therapy for Neuroblastoma","volume":"19","author":"Qiu","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.annonc.2019.11.011","article-title":"Extended Induction Chemotherapy Does Not Improve the Outcome for High-Risk Neuroblastoma Patients: Results of the Randomized Open-Label GPOH Trial NB2004-HR","volume":"31","author":"Berthold","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.annonc.2019.12.003","article-title":"High-Risk Neuroblastoma: Where Do We Go?","volume":"31","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.semcancer.2011.07.002","article-title":"Progress in Treatment and Risk Stratification of Neuroblastoma: Impact on Future Clinical and Basic Research","volume":"21","author":"Eggert","year":"2011","journal-title":"Semin. Cancer Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhao, W., Han, Y., Yu, X., Liu, J., Zhang, J., and Li, J. (2025). Development of Intelligent Tools to Predict Neuroblastoma Risk Stratification and Overall Prognosis Based on Multiphase Enhanced CT and Clinical Features. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1573398"},{"key":"ref_9","first-page":"102198","article-title":"Machine Learning-Derived Lysosome-Dependent Cell Death Signatures for Prognostic Stratification and Immune Microenvironment Assessment in Neuroblastoma","volume":"19","author":"Zi","year":"2026","journal-title":"J. Radiat. Res. Appl. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.cell.2024.12.014","article-title":"Systems-Level Immunomonitoring in Children with Solid Tumors to Enable Precision Medicine","volume":"188","author":"Chen","year":"2025","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic Regulation of Gene Expression by Histone Lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e70070","DOI":"10.1002\/ctm2.70070","article-title":"Lactylation in Cancer: Mechanisms in Tumour Biology and Therapeutic Potentials","volume":"14","author":"He","year":"2024","journal-title":"Clin. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114957","DOI":"10.1016\/j.celrep.2024.114957","article-title":"H3K9 Lactylation in Malignant Cells Facilitates CD8+ T Cell Dysfunction and Poor Immunotherapy Response","volume":"43","author":"Wang","year":"2024","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113688","DOI":"10.1016\/j.celrep.2024.113688","article-title":"Histone Lactylation Inhibits RAR\u03b3 Expression in Macrophages to Promote Colorectal Tumorigenesis through Activation of TRAF6-IL-6-STAT3 Signaling","volume":"43","author":"Li","year":"2024","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102670","DOI":"10.1016\/j.arr.2025.102670","article-title":"Lactylation: The Metabolic Accomplice Shaping Cancer\u2019s Response to Radiotherapy and Immunotherapy","volume":"104","author":"Yu","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2404899122","DOI":"10.1073\/pnas.2404899122","article-title":"Dynamic Investigation of Hypoxia-Induced L-Lactylation","volume":"122","author":"Gao","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s12276-025-01410-7","article-title":"Protein Lactylation in Cancer: Mechanisms and Potential Therapeutic Implications","volume":"57","author":"Rho","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41580-025-00876-7","article-title":"Biochemistry and Regulation of Histone Lysine L-Lactylation","volume":"27","author":"Sheng","year":"2026","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"mjae056","DOI":"10.1093\/jmcb\/mjae056","article-title":"DNAJC12 Downregulation Induces Neuroblastoma Progression via Increased Histone H4K5 Lactylation","volume":"16","author":"Yang","year":"2024","journal-title":"J. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s10565-026-10154-7","article-title":"NAA20-Mediated ACF1 Lactylation Drives Neuroblastoma Progression through Enhancing GCLM-Dependent Glutathione Synthesis","volume":"42","author":"Han","year":"2026","journal-title":"Cell Biol. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13578-026-01538-7","article-title":"Lactylation-Related Gene Signature as a Prognostic Biomarker for Neuroblastoma: Insights into Tumor Progression and Immune Modulation","volume":"16","author":"Zhu","year":"2026","journal-title":"Cell Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12285","DOI":"10.1007\/s00432-023-05110-5","article-title":"A Practical Nomogram and Risk Stratification System for Predicting Survival Outcomes in Neuroblastoma Patients: A SEER Population-Based Study","volume":"149","author":"Zhuo","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41587-020-00795-2","article-title":"Delineating Copy Number and Clonal Substructure in Human Tumors from Single-Cell Transcriptomes","volume":"39","author":"Gao","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_24","first-page":"255","article-title":"Progress of Research on the Mechanism of Enolase 1 in Regulating Tumors and Targeting Intervention","volume":"49","author":"Xie","year":"2025","journal-title":"Prog. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the Origin of Cancer Cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.ccell.2020.08.014","article-title":"Single-Cell Characterization of Malignant Phenotypes and Developmental Trajectories of Adrenal Neuroblastoma","volume":"38","author":"Dong","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/nsmb.2880","article-title":"Structure of Cohesin Subcomplex Pinpoints Direct Shugoshin-Wapl Antagonism in Centromeric Cohesion","volume":"21","author":"Hara","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1074\/jbc.RA118.005978","article-title":"Aurora B Kinase Activity\u2013Dependent and \u2013Independent Functions of the Chromosomal Passenger Complex in Regulating Sister Chromatid Cohesion","volume":"294","author":"Yi","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_29","unstructured":"Sundaramoorthy, S. (2014). Mediators of Pre-mRNA Splicing Regulate Sister Chromatid Cohesion in Mammalian Cells. [Ph.D. Thesis, UCL (University College London)]."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/35036614","article-title":"Role for the P53 Homologue P73 in E2F-1-Induced Apoptosis","volume":"407","author":"Irwin","year":"2000","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00018-022-04659-7","article-title":"Chromodomain on Y-like 2 (CDYL2) Implicated in Mitosis and Genome Stability Regulation via Interaction with CHAMP1 and POGZ","volume":"80","author":"Siouda","year":"2023","journal-title":"Cell Mol. Life Sci."},{"key":"ref_32","unstructured":"Yeh, C.C.-J. (2016). Regulation of Chromosome Segregation and Cohesion by the Deubiquitinase USP37. [Ph.D. Thesis, University of Toronto]."},{"key":"ref_33","first-page":"57","article-title":"Progresses on the structure and function of cohesin","volume":"42","author":"Zhang","year":"2020","journal-title":"Hereditas"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1747-1028-7-10","article-title":"The Retinoblastoma Family of Proteins and Their Regulatory Functions in the Mammalian Cell Division Cycle","volume":"7","author":"Henley","year":"2012","journal-title":"Cell Div."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"W\u00f6rthm\u00fcller, J., Disler, S., Pradervand, S., Richard, F., Haerri, L., Ruiz Buend\u00eda, G.A., Fournier, N., Desmedt, C., and R\u00fcegg, C. (2023). MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer. Cells, 12.","DOI":"10.3390\/cells12151929"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Nicolay, B.N., Bayarmagnai, B., Moon, N.S., Benevolenskaya, E.V., and Frolov, M.V. (2010). Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1000918"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1080\/15384101.2015.1044172","article-title":"Two-Way Communication between the Metabolic and Cell Cycle Machineries: The Molecular Basis","volume":"14","author":"Kaplon","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1038\/cdd.2008.135","article-title":"E2F1 Controls Alternative Splicing Pattern of Genes Involved in Apoptosis through Upregulation of the Splicing Factor SC35","volume":"15","author":"Merdzhanova","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jung, Y., Cho, J.H., Park, S., Kang, M., Park, S., Choi, D.H., Jeong, M., Park, K.C., Yeom, Y.I., and Lee, D.C. (2019). Lactate Activates the E2F Pathway to Promote Cell Motility by Up-Regulating Microtubule Modulating Genes. Cancers, 11.","DOI":"10.3390\/cancers11030274"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/1476-4598-9-124","article-title":"HOXB13 Promotes Androgen Independent Growth of LNCaP Prostate Cancer Cells by the Activation of E2F Signaling","volume":"9","author":"Kim","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.tibs.2004.06.006","article-title":"E2F Target Genes: Unraveling the Biology","volume":"29","author":"Bracken","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Xu, Y., Zhang, C., Wu, J., Guo, P., Jiang, N., Wang, C., and Feng, Y. (2025). Integrated Analysis of Single-Cell RNA-Seq and Spatial Transcriptomics to Identify the Lactylation-Related Protein TUBB2A as a Potential Biomarker for Glioblastoma in Cancer Cells by Machine Learning. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1601533"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s13059-015-0694-1","article-title":"Comparison of RNA-Seq and Microarray-Based Models for Clinical Endpoint Prediction","volume":"16","author":"Zhang","year":"2015","journal-title":"Genome Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.15252\/embj.201695607","article-title":"Drosophila Dalmatian Combines Sororin and Shugoshin Roles in Establishment and Protection of Cohesion","volume":"36","author":"Yamada","year":"2017","journal-title":"EMBO J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8327","DOI":"10.1039\/D3SC01874A","article-title":"Regulating Tumor Glycometabolism and the Immune Microenvironment by Inhibiting Lactate Dehydrogenase with Platinum(Iv) Complexes","volume":"14","author":"Jin","year":"2023","journal-title":"Chem. Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/13\/2280\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:27:02Z","timestamp":1783484822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/13\/2280"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":45,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["molecules31132280"],"URL":"https:\/\/doi.org\/10.3390\/molecules31132280","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]}}}