{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:33:29Z","timestamp":1786700009455,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Nucleotide metabolism in clear cell renal cell carcinoma (ccRCC) remains understudied. Elucidating its heterogeneous characteristics and key genes may provide new insights for prognostic assessment and targeted therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      By integrating scRNA-seq with bulk RNA-seq data, we first screened for nucleotide metabolism-related genes (NMRGs) using five machine learning algorithms. NMRGs signature was then constructed using 101 machine learning algorithms to optimize clinical prognosis assessment. The selected NMRGs were subjected to GO functional annotation and KEGG pathway enrichment analysis. Finally, the functional role of the key gene IFI30 was validated through both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The NMRG signature constructed using 101 machine learning algorithms outperformed traditional clinical parameters and 122 published models across multiple independent cohorts. High-risk patients exhibited significantly worse overall survival. Enrichment analysis showed that IFI30 and its associated genes were significantly enriched in nucleotide metabolism pathways. Immunohistochemistry confirmed high IFI30 expression in ccRCC tumor tissues. Functional assays demonstrated that IFI30 knockdown suppressed ccRCC cell proliferation, migration, invasion, and tumorigenicity, while inducing apoptosis. In addition, IFI30 knockdown downregulated PRPS1\/2, a key rate-limiting enzyme in nucleotide synthesis, and nucleotide rescue experiments reversed the phenotypic suppression, confirming that IFI30 promotes ccRCC progression through nucleotide metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study developed an NMRGs signature that outperforms existing models and, for the first time, reveals that IFI30 promotes ccRCC malignant progression by regulating nucleotide metabolism. These findings provide a new theoretical basis for prognostic assessment and metabolism-targeted therapy in ccRCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1881692","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:54:50Z","timestamp":1786697690000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative analysis of scRNA-seq and bulk RNA-seq with machine learning develops a nucleotide metabolism\u2013based prognostic model for ccRCC and reveals the function of IFI30"],"prefix":"10.3389","volume":"16","author":[{"given":"Qiao","family":"Lyu","sequence":"first","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhenXiong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiaHui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"QiYu","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuoHao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HanDa","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JianSheng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DongMing","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital)","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LiJun","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-019-00676-y","article-title":"First-line systemic therapy for metastatic clear-cell renal cell carcinoma: Critical appraisal of emerging options","volume":"14","author":"Loo","year":"2019","journal-title":"Target Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.euf.2025.04.001","article-title":"Management of metastatic renal cell carcinoma: Guideline updates","volume":"11","author":"Barragan-Carrillo","year":"2025","journal-title":"Eur Urol Focus"},{"key":"B4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/s41581-025-00983-w","article-title":"Immunological features of clear-cell renal-cell carcinoma and resistance to immune checkpoint inhibitors","volume":"21","author":"Burgers","year":"2025","journal-title":"Nat Rev Nephrol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfae036","article-title":"Global epidemiology of kidney cancer","volume":"39","author":"Cirillo","year":"2024","journal-title":"Nephrol Dial Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.05.005","article-title":"Tumor cell metabolism: Cancer's Achilles' heel","volume":"13","author":"Kroemer","year":"2008","journal-title":"Cancer Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41585-022-00654-6","article-title":"Fatty acid metabolism reprogramming in ccrcc: Mechanisms and potential targets","volume":"20","author":"Tan","year":"2023","journal-title":"Nat Rev Urol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.84399","article-title":"P32 regulates glycometabolism and tca cycle to inhibit ccrcc progression via copper-induced dlat lipoylation oligomerization","volume":"20","author":"Tian","year":"2024","journal-title":"Int J Biol Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.59","article-title":"Metabolic reprogramming in clear cell renal cell carcinoma","volume":"13","author":"Wettersten","year":"2017","journal-title":"Nat Rev Nephrol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The emerging hallmarks of cancer metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-023-00557-7","article-title":"Nucleotide metabolism: A pan-cancer metabolic dependency","volume":"23","author":"Mullen","year":"2023","journal-title":"Nat Rev Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.122.000856","article-title":"Cell and tissue specific metabolism of nucleoside and nucleotide drugs: Case studies and implications for precision medicine","volume":"51","author":"To","year":"2023","journal-title":"Drug Metab Dispos"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202416809","article-title":"Ledgf binds H3r17me2a promoting de novo nucleotide biosynthesis in setd2 mutant clear cell renal cell carcinoma","volume":"12","author":"Zhang","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2025-013025","article-title":"Trim28 drives immune evasion via parp1 sumoylation and nad(+) depletion in clear cell renal cell carcinoma","volume":"13","author":"Zhan","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.4c08055","article-title":"Engineered biomimetic nanovesicles synergistically remodel folate-nucleotide and \u03b3-aminobutyric acid metabolism to overcome sunitinib-resistant renal cell carcinoma","volume":"18","author":"Lv","year":"2024","journal-title":"ACS Nano"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2017.1329068","article-title":"Machine learning for epigenetics and future medical applications","volume":"12","author":"Holder","year":"2017","journal-title":"Epigenetics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for rna-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"015010","DOI":"10.1088\/1361-6560\/ab6177","article-title":"Combat harmonization for radiomic features in independent phantom and lung cancer patient computed tomography datasets","volume":"65","author":"Mahon","year":"2020","journal-title":"Phys Med Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0329549","article-title":"Identification of immune-related biomarkers associated with allergic rhinitis and development of a sample diagnostic model","volume":"20","author":"Wang","year":"2025","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","first-page":"21195","DOI":"10.1038\/s41598-024-70659-1","article-title":"Comprehensive analysis of scrna-seq and bulk rna-seq reveals ubiquitin promotes pulmonary fibrosis in chronic pulmonary diseases","volume":"14","author":"Wen","year":"2024","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1109\/TNSRE.2018.2838075","article-title":"Mapping the cortical network arising from up-regulated amygdaloidal activation using -louvain algorithm","volume":"26","author":"Liu","year":"2018","journal-title":"IEEE Trans Neural Syst Rehabil Eng"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1101\/gr.251447.119","article-title":"Exploring dimension-reduced embeddings with sleepwalk","volume":"30","author":"Ovchinnikova","year":"2020","journal-title":"Genome Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13409","article-title":"An artificial intelligence network-guided signature for predicting outcome and immunotherapy response in lung adenocarcinoma patients based on 26 machine learning algorithms","volume":"56","author":"Zhang","year":"2023","journal-title":"Cell Prolif"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.7150\/thno.121257","article-title":"Single-cell and spatial transcriptomics reveal p4ha2-mediated radiotherapy resistance mechanisms in breast cancer","volume":"16","author":"Li","year":"2026","journal-title":"Theranostics"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2015.12.029","article-title":"Roc-ing along: Evaluation and interpretation of receiver operating characteristic curves","volume":"159","author":"Carter","year":"2016","journal-title":"Surgery"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1177\/09731296241262075","article-title":"Ganoderic acid a suppresses androgenindependent cell growth via the akt\/gsk-3\u03b2\/\u03b2-catenin signaling pathway","volume":"21","author":"Lyu","year":"2025","journal-title":"Pharmacogn Mag"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2017.46","article-title":"Limited nucleotide pools restrict Epstein-Barr virus-mediated B-cell immortalization","volume":"6","author":"Hafez","year":"2017","journal-title":"Oncogenesis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/s0021-9258(18)37889-x","article-title":"Molecular and biochemical characterization of a novel gamma-interferon-inducible protein","volume":"263","author":"Luster","year":"1988","journal-title":"J Biol Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1523854","article-title":"Comprehensive single-cell pan-cancer atlas unveils Ifi30+ macrophages as key modulators of intra-tumoral immune dynamics","volume":"16","author":"Jiang","year":"2025","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2023.103008","article-title":"Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function","volume":"84","author":"Madsen","year":"2023","journal-title":"Curr Opin Biotechnol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1186\/s12967-024-05495-y","article-title":"Spatial transcriptome and single-cell reveal the role of nucleotide metabolism in colorectal cancer progression and tumor microenvironment","volume":"22","author":"Liu","year":"2024","journal-title":"J Transl Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12822","article-title":"Edoctor: Machine learning and the future of medicine","volume":"284","author":"Handelman","year":"2018","journal-title":"J Intern Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.648134","article-title":"Timp1 indicates poor prognosis of renal cell carcinoma and accelerates tumorigenesis via emt signaling pathway","volume":"13","author":"Shou","year":"2022","journal-title":"Front Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.834524","article-title":"Identification of plaUR-related cerna and immune prognostic signature for kidney renal clear cell carcinoma","volume":"12","author":"Wang","year":"2022","journal-title":"Front Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20230420","article-title":"An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis","volume":"221","author":"Folkert","year":"2024","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102540","article-title":"Screening, identification and validation of ccnd1 and pecam1\/cd31 for predicting prognosis in renal cell carcinoma patients","volume":"11","author":"Yang","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4084\/mjhid.2013.060","article-title":"Von Willebrand factor, angiodysplasia and angiogenesis","volume":"5","author":"Randi","year":"2013","journal-title":"Mediterr J Hematol Infect Dis"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1007\/s12672-025-03066-1","article-title":"The role of Jpt1 in hepatocellular carcinoma: Tumor progression, microtubule dynamics regulation, and potential mechanisms within the immune microenvironment","volume":"16","author":"Lu","year":"2025","journal-title":"Discov Oncol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2025.101005","article-title":"Ifi30 promotes tumor-associated macrophage infiltration via activation of the atf3-ccl5 axis in breast cancer","volume":"6","author":"Ren","year":"2025","journal-title":"Innovation (Camb)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.2147\/ott.S237162","article-title":"Ifi30 is a novel immune-related target with predicting value of prognosis and treatment response in glioblastoma","volume":"13","author":"Zhu","year":"2020","journal-title":"Onco Targets Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14334","article-title":"Interferon-\u03b3 inducible protein 30 promotes the epithelial-mesenchymal transition-like phenotype and chemoresistance by activating egfr\/akt\/gsk3\u03b2\/\u03b2-catenin pathway in glioma","volume":"29","author":"Chen","year":"2023","journal-title":"CNS Neurosci Ther"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001736RR","article-title":"Modulation of adenine phosphoribosyltransferase-mediated salvage pathway to accelerate diabetic wound healing","volume":"35","author":"Young","year":"2021","journal-title":"FASEB J"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2022.102947","article-title":"Generation of a human ipsc line bchnci001-a from a patient with uridine-responsive epileptic encephalopathy carrying biallelic cad mutations","volume":"65","author":"Zhou","year":"2022","journal-title":"Stem Cell Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1881692\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:54:52Z","timestamp":1786697692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1881692\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":44,"alternative-id":["10.3389\/fonc.2026.1881692"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1881692","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"article-number":"1881692"}}