{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:13:43Z","timestamp":1786115623992,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"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. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background and aim<\/jats:title>\n                    <jats:p>Lactylation is a novel histone modification driven by lactate accumulation, which has been implicated in clear cell renal cell carcinoma (ccRCC) progression. However, its comprehensive molecular mechanism and clinical relevance remain poorly understood. This study aimed to investigate lactylation-related molecular mechanisms and therapeutic responses in ccRCC using integrated single-cell analysis and machine learning algorithms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated single-cell RNA sequencing and bulk transcriptomic data from patients with ccRCC. Transcriptional signatures of lactylation-related genes were evaluated using four gene set scoring algorithms. Key lactylation-related genes were identified through weighted gene co-expression network analysis and differential expression analysis. A prognostic model was constructed using 10 machine learning algorithms and subsequently validated in independent cohorts. The functional role of the core gene,\n                      <jats:italic>CDT1<\/jats:italic>\n                      , was validated through\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>\n                      We established a prognostic model comprising 13 lactylation-related genes. The model robustly stratified patients into high- and low-risk groups with distinct survival outcomes, immune microenvironment features, and immunotherapy responses. Functional assays revealed that\n                      <jats:italic>CDT1<\/jats:italic>\n                      , the core gene of the signature, promoted ccRCC cell proliferation, migration, and invasion. Moreover, modulation of CDT1 altered intracellular L-lactate levels. However, whether this effect reflects a direct metabolic\u2013epigenetic regulatory mechanism or is secondary to proliferative changes remains to be elucidated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study delineates the molecular heterogeneity associated with lactylation-related gene expression in ccRCC and presents a validated prognostic model. It identifies\n                      <jats:italic>CDT1<\/jats:italic>\n                      as a novel oncogene and potential biomarker, providing insights into metabolic\u2013epigenetic crosstalk and a foundation for future therapeutic development.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1883553","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:24:35Z","timestamp":1785990275000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating single-cell analysis and machine learning algorithms to explore lactylation-related molecular mechanisms and therapeutic responses in clear cell renal cell carcinoma and identifying CDT1 as a potential biomarker"],"prefix":"10.3389","volume":"17","author":[{"given":"Yue","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]},{"name":"Urologic Cancer Institute, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bihui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai Fourth People\u2019s Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianchao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Affiliated Hospital of Anhui Medical University","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangli","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]},{"name":"Urologic Cancer Institute, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"Ca: A Cancer J For Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2022.06.016","article-title":"The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part a: Renal, penile, and testicular tumours","volume":"82","author":"Moch","year":"2022","journal-title":"Eur Urol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s12943-024-02059-y","article-title":"Pd1\/pd-l1 blockade in clear cell renal cell carcinoma: Mechanistic insights, clinical efficacy, and future perspectives","volume":"23","author":"Zhu","year":"2024","journal-title":"Mol Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-24-1378","article-title":"Requirement for cyclin D1 underlies cell-autonomous HIF2 dependence in kidney cancer","volume":"15","author":"Shirole","year":"2025","journal-title":"Cancer Discov"},{"key":"B5","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.semcancer.2020.03.012","article-title":"Coalescing lessons from oxygen sensing, tumor metabolism, and epigenetics to target VHL loss in kidney cancer","volume":"67","author":"Chakraborty","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14704","article-title":"Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: A meta-analysis and review","volume":"8","author":"Kim","year":"2017","journal-title":"Oncotarget"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202509654","article-title":"Er\u03b2\/circAHNAK axis inhibits USP10-FMR1 deubiquitination to prevent m6A-mediated ADAM17 decay and promote angiogenesis in clear cell renal cell carcinoma","volume":"12","author":"Xu","year":"2025","journal-title":"Advanced Sci (Weinheim Baden-W\u00fcrttemberg Germany)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02519-z","article-title":"Lactate: Elucidating its indispensable role in human health","volume":"25","author":"Zhang","year":"2026","journal-title":"Mol Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.218209","article-title":"Lactic acid promotes an MDSC-like phenotype via HIF1\u03b1 stabilization with impact on prognosis in renal cell carcinoma","volume":"639","author":"Babl","year":"2025","journal-title":"Cancer Lett"},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13148-024-01682-2","article-title":"Lactylation: The novel histone modification influence on gene expression, protein function, and disease","volume":"16","author":"Hu","year":"2024","journal-title":"Clin Epigenet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-022-01637-w","article-title":"Lactylation: A passing fad or the future of posttranslational modification","volume":"45","author":"Xin","year":"2022","journal-title":"Inflammation"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.73398","article-title":"A positive feedback loop between inactive VHL-triggered histone lactylation and PDGFR\u03b2 signaling drives clear cell renal cell carcinoma progression","volume":"18","author":"Yang","year":"2022","journal-title":"Int J Biol Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s40364-025-00811-0","article-title":"Single-cell sequencing technology in renal cancer: Insights into tumor biology and clinical application","volume":"13","author":"Zhang","year":"2025","journal-title":"biomark Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"4790","DOI":"10.1016\/j.cell.2024.06.038","article-title":"Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes","volume":"187","author":"Yang","year":"2024","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1647384","article-title":"Integrative single-cell and machine learning analysis predicts lactylation-driven therapy resistance in prostate cancer: A molecular docking and experiments-validated framework for treatment optimization","volume":"16","author":"Liu","year":"2025","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1084531","article-title":"Identification and validation of immune and oxidative stress-related diagnostic markers for diabetic nephropathy by WGCNA and machine learning","volume":"14","author":"Xu","year":"2023","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412747","article-title":"Histone lactylation antagonizes senescence and skeletal muscle aging by modulating aging-related pathways","volume":"12","author":"Meng","year":"2025","journal-title":"Advanced Sci (Weinheim Baden-W\u00fcrttemberg Germany)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2026.01.007","article-title":"Lactylation at the metabolic-epigenetic interface in cardiovascular diseases: Context-dependent mechanisms and translational roadmap","author":"Cheng","year":"2026","journal-title":"J Adv Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1186\/s12967-025-07350-0","article-title":"Histone modification-mediated epigenetic regulation in AKI-to-CKD transition: A cell-type-specific perspective","volume":"23","author":"Chai","year":"2025","journal-title":"J Transl Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s12943-025-02392-w","article-title":"Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation","volume":"24","author":"Lin","year":"2025","journal-title":"Mol Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202415309","article-title":"MeCP2 lactylation protects against ischemic brain injury by transcriptionally regulating neuronal apoptosis","volume":"12","author":"Sun","year":"2025","journal-title":"Advanced Sci (Weinheim Baden-W\u00fcrttemberg Germany)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202413709","article-title":"UGDH lactylation aggravates osteoarthritis by suppressing glycosaminoglycan synthesis and orchestrating nucleocytoplasmic transport to activate MAPK signaling","volume":"12","author":"Lan","year":"2025","journal-title":"Advanced Sci (Weinheim Baden-W\u00fcrttemberg Germany)"},{"key":"B24","doi-asserted-by":"crossref","DOI":"10.1016\/j.jare.2025.10.008","article-title":"Mitigation of renal tubular injury by SIRT6 may improve individual outcomes in diabetic kidney disease-potential mechanisms involving epigenetic repression of inflammatory responses","volume":"85","author":"Jin","year":"2026","journal-title":"J Adv Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/imna-d-24-00018","article-title":"New insights into the use of traditional Chinese medicine for treating diabetic kidney disease by regulating DNA methylation","volume":"11","author":"Ma","year":"2024","journal-title":"Integr Med Nephrol Androl"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.7150\/thno.104858","article-title":"Targeting platinum-resistant ovarian cancer by disrupting histone and RAD51 lactylation","volume":"15","author":"Sun","year":"2025","journal-title":"Theranostics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s13167-023-00327-3","article-title":"Multi-omics identification of an immunogenic cell death-related signature for clear cell renal cell carcinoma in the context of 3P medicine and based on a 101-combination machine learning computational framework","volume":"14","author":"Liu","year":"2023","journal-title":"EPMA J"},{"key":"B28","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41597-024-03551-2","article-title":"Integrated machine learning algorithms reveal a bone metastasis-related signature of circulating tumor cells in prostate cancer","volume":"11","author":"Ren","year":"2024","journal-title":"Sci Data"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26550","article-title":"Low NR3C2 levels correlate with aggressive features and poor prognosis in non-distant metastatic clear-cell renal cell carcinoma","volume":"233","author":"Zhao","year":"2018","journal-title":"J Cell Physiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1159\/000521745","article-title":"MicroRNA-155-5p targets NR3C2 to promote Malignant progression of clear cell renal cell carcinoma","volume":"47","author":"Yan","year":"2022","journal-title":"Kidney Blood Pressure Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-16-0348","article-title":"KLF6 suppresses metastasis of clear cell renal cell carcinoma via transcriptional repression of E2F1","volume":"77","author":"Gao","year":"2017","journal-title":"Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217148","article-title":"SMEK1 promotes clear cell renal cell carcinoma progression via EGFR tyrosine-kinase dependent pathway","volume":"601","author":"Wang","year":"2024","journal-title":"Cancer Lett"},{"key":"B33","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.canlet.2021.05.012","article-title":"E2F1 promotes proliferation and metastasis of clear cell renal cell carcinoma via activation of SREBP1-dependent fatty acid biosynthesis","volume":"514","author":"Shen","year":"2021","journal-title":"Cancer Lett"},{"key":"B34","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/s43018-021-00316-3","article-title":"SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes","volume":"3","author":"Xie","year":"2022","journal-title":"Nat Cancer"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.93201","article-title":"SETD7 promotes cell proliferation and migration via methylation-mediated TAF7 in clear cell renal cell carcinoma","volume":"20","author":"Zhang","year":"2024","journal-title":"Int J Biol Sci"},{"key":"B36","doi-asserted-by":"publisher","first-page":"8268","DOI":"10.1038\/s41467-025-63669-8","article-title":"Temporal control of human DNA replication licensing by CDK4\/6-RB signalling and chemical genetics","volume":"16","author":"Sosenko Piscitello","year":"2025","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2210\/pdb5udb\/pdb","article-title":"Structural basis of Mcm2-7 replicative helicase loading by ORC-Cdc6 and Cdt1","volume":"24","author":"Yuan","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.218186","article-title":"CDT1 induces the formation of polyploid giant cancer cells and promotes centrosome amplification through the PLK4\/SASS6 axis","volume":"639","author":"Pan","year":"2026","journal-title":"Cancer Lett"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2426743122","article-title":"BRCA2 reversion mutation-independent resistance to PARP inhibition through impaired DNA prereplication complex function","volume":"122","author":"Pappas","year":"2025","journal-title":"PNAS"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02082-x","article-title":"Lactate and lactylation in cancer","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1496390","article-title":"Lactate: A rising star in tumors and inflammation","volume":"15","author":"Liu","year":"2024","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01985-9","article-title":"Histone lactylation drives CD8(+) T cell metabolism and function","volume":"25","author":"Raychaudhuri","year":"2024","journal-title":"Nat Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.molimm.2022.12.015","article-title":"Effects of lactate on metabolism and differentiation of CD4(+)T cells","volume":"154","author":"Zhang","year":"2023","journal-title":"Mol Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.162","article-title":"T-cell exhaustion in the tumor microenvironment","volume":"6","author":"Jiang","year":"2015","journal-title":"Cell Death Dis"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1883553\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:24:36Z","timestamp":1785990276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1883553\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":44,"alternative-id":["10.3389\/fendo.2026.1883553"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1883553","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"article-number":"1883553"}}