{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:41:25Z","timestamp":1778200885692,"version":"3.51.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"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. Pharmacol."],"abstract":"<jats:p>DLD is a key gene involved in \u201ccuproptosis,\u201d but its roles in tumor progression and immunity remain unclear. Exploring the potential mechanisms and biological roles of DLD may provide new insights for therapeutic strategies for tumors. In the present study, we analyzed the role of DLD in a variety of tumors by using several bioinformatic tools. The results showed that compared with normal tissues, tumor tissues representing multiple cancers showed significant differential expression of DLD. High DLD expression was associated with a good prognosis in BRCA, KICH, and LUAD. Conversely, high expression levels of DLD were detrimental to patient prognosis in many other tumors, such as COAD, KIRC, and KIRP. In addition, the associations of DLD with infiltrating immune cells, genetic alterations and methylation levels across cancers were assessed. Aberrant expression of DLD was positively correlated with most infiltrating immune cells, especially neutrophils. The DLD methylation level was significantly decreased in COAD, LIHC, and LUSC but significantly increased in BRCA. DLD had the highest mutation rate (6.04%) in ESCA. In LUSC, patients with genetic alterations in DLD showed a poorer prognosis. At the single-cell level, the roles of DLD in regulating cancer-associated biological functions, such as metastasis, inflammation, and differentiation, were explored. Afterward, we further investigated whether several disease-associated genes could be correlated with DLD. GO enrichment analysis indicated that DLD-related genes were mainly associated with mitochondria-related cellular components, aerobic respiration and the tricarboxylic acid cycle. Finally, the correlations between DLD expression and immunomodulatory genes, immune checkpoints, and sensitivity to some antitumor drugs were investigated. It is worth noting that DLD expression was positively correlated with immune checkpoint genes and immunomodulatory genes in most cancers. In conclusion, this study comprehensively analyzed the differential expression, prognostic value and immune cell infiltration-related function of DLD across cancers. Our results suggest that DLD has great potential to serve as a candidate marker for pancancer prognosis and immunotherapy and may provide a new direction for cancer treatment development.<\/jats:p>","DOI":"10.3389\/fphar.2023.1111462","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T04:24:20Z","timestamp":1680495860000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Comprehensive analysis of the cuproptosis-related gene DLD across cancers: A potential prognostic and immunotherapeutic target"],"prefix":"10.3389","volume":"14","author":[{"given":"Weiguang","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linjian","family":"Tong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lixia","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiming","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1016\/j.bbadis.2016.08.013","article-title":"Structural alterations induced by ten disease-causing mutations of human dihydrolipoamide dehydrogenase analyzed by hydrogen\/deuterium-exchange mass spectrometry: Implications for the structural basis of E3 deficiency","volume":"1862","author":"Ambrus","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"B2","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1038\/s41419-018-0802-8","article-title":"\u03b1-Ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis","volume":"9","author":"Atlante","year":"2018","journal-title":"Cell Death Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"B4","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"Ualcan: An update to the integrated cancer data analysis platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"B5","doi-asserted-by":"publisher","first-page":"5679","DOI":"10.1038\/s41467-019-13528-0","article-title":"Pan-cancer molecular subtypes revealed by mass-spectrometry-based proteomic characterization of more than 500 human cancers","volume":"10","author":"Chen","year":"2019","journal-title":"Nat. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/s41392-022-01229-y","article-title":"Copper homeostasis and cuproptosis in health and disease","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. Target Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"912037","DOI":"10.3389\/fgene.2022.912037","article-title":"Identification and validation of cuproptosis-related prognostic signature and associated regulatory Axis in uterine Corpus endometrial carcinoma","volume":"13","author":"Chen","year":"2022","journal-title":"Front. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"975695","DOI":"10.3389\/fimmu.2022.975695","article-title":"Emerging trends and research foci of oncolytic virotherapy for central nervous system tumors: A bibliometric study","volume":"13","author":"Cheng","year":"2022","journal-title":"Front. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1016\/j.molcel.2022.05.001","article-title":"Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death","volume":"82","author":"Cobine","year":"2022","journal-title":"Mol. Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"7451","DOI":"10.1007\/s00018-021-03996-3","article-title":"Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis","volume":"78","author":"Duarte","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e2924","DOI":"10.1002\/jmr.2924","article-title":"The moonlighting activities of dihydrolipoamide dehydrogenase: Biotechnological and biomedical applications","volume":"34","author":"Fleminger","year":"2021","journal-title":"J. Mol. Recognit."},{"key":"B12","doi-asserted-by":"publisher","first-page":"D808","DOI":"10.1093\/nar\/gks1094","article-title":"STRING v9.1: Protein-protein interaction networks, with increased coverage and integration","volume":"41","author":"Franceschini","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/nm.4336","article-title":"Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia","volume":"23","author":"Giustacchini","year":"2017","journal-title":"Nat. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"4557","DOI":"10.1158\/0008-5472.CAN-18-3962","article-title":"The tumor microenvironment innately modulates cancer progression","volume":"79","author":"Hinshaw","year":"2019","journal-title":"Cancer Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3089","DOI":"10.7150\/thno.53649","article-title":"Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer","volume":"11","author":"Hu","year":"2021","journal-title":"Theranostics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.7150\/thno.33800","article-title":"The miR-26a\/AP-2\u03b1\/Nanog signaling axis mediates stem cell self-renewal and temozolomide resistance in glioma","volume":"9","author":"Huang","year":"2019","journal-title":"Theranostics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41586-020-1969-6","article-title":"pan-cancer analysis of whole genomes","volume":"578","year":"2020","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/s41568-020-0281-y","article-title":"Neutrophil diversity and plasticity in tumour progression and therapy","volume":"20","author":"Jaillon","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"B20","doi-asserted-by":"publisher","first-page":"9004830","DOI":"10.1155\/2022\/9004830","article-title":"Database mining detected a cuproptosis-related prognostic signature and a related regulatory Axis in breast cancer","volume":"2022","author":"Jiang","year":"2022","journal-title":"Dis. Markers"},{"key":"B21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.cmet.2006.02.002","article-title":"HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia","volume":"3","author":"Kim","year":"2006","journal-title":"Cell Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"930041","DOI":"10.3389\/fphar.2022.930041","article-title":"Comprehensive analysis of cuproptosis-related genes in immune infiltration and prognosis in melanoma","volume":"13","author":"Lv","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.20892\/j.issn.2095-3941.2022.0231","article-title":"Current cancer burden in China: Epidemiology, etiology, and prevention","volume":"19","author":"Maomao","year":"2022","journal-title":"Cancer Biol. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nri.2017.49","article-title":"Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy","volume":"17","author":"Nagarsheth","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1126\/science.1254257","article-title":"Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma","volume":"344","author":"Patel","year":"2014","journal-title":"Science"},{"key":"B27","doi-asserted-by":"publisher","first-page":"784","DOI":"10.3389\/fimmu.2020.00784","article-title":"The tumor microenvironment in the response to immune checkpoint blockade therapies","volume":"11","author":"Petitprez","year":"2020","journal-title":"Front. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"B29","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.gde.2009.10.009","article-title":"HIF-1: Upstream and downstream of cancer metabolism","volume":"20","author":"Semenza","year":"2010","journal-title":"Curr. Opin. Genet. Dev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"Gepia: A web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The immune landscape of cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/nature20123","article-title":"Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma","volume":"539","author":"Tirosh","year":"2016","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","first-page":"eaai8478","DOI":"10.1126\/science.aai8478","article-title":"Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq","volume":"355","author":"Venteicher","year":"2017","journal-title":"Science"},{"key":"B35","doi-asserted-by":"publisher","first-page":"998236","DOI":"10.3389\/fimmu.2022.998236","article-title":"The cuproptosis-related signature associated with the tumor environment and prognosis of patients with glioma","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"646311","DOI":"10.3389\/fcell.2021.646311","article-title":"Global research trends of ferroptosis: A rapidly evolving field with enormous potential","volume":"9","author":"Wu","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"962028","DOI":"10.3389\/fgene.2022.962028","article-title":"Prognostic and immunological role of cuproptosis-related protein FDX1 in pan-cancer","volume":"13","author":"Xiao","year":"2022","journal-title":"Front. Genet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.mad.2008.01.006","article-title":"Changes in dihydrolipoamide dehydrogenase expression and activity during postnatal development and aging in the rat brain","volume":"129","author":"Yan","year":"2008","journal-title":"Mech. Ageing Dev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3707","DOI":"10.7150\/thno.25166","article-title":"AP-2\u03b2 inhibits hepatocellular carcinoma invasion and metastasis through Slug and Snail to suppress epithelial-mesenchymal transition","volume":"8","author":"Yang","year":"2018","journal-title":"Theranostics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1015094","DOI":"10.3389\/fonc.2022.1015094","article-title":"A cuproptosis-related genes signature associated with prognosis and immune cell infiltration in osteosarcoma","volume":"12","author":"Yang","year":"2022","journal-title":"Front. Oncol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"D900","DOI":"10.1093\/nar\/gky939","article-title":"CancerSEA: A cancer single-cell state atlas","volume":"47","author":"Yuan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.freeradbiomed.2020.11.037","article-title":"Downregulation of dihydrolipoyl dehydrogenase by UVA suppresses melanoma progression via triggering oxidative stress and altering energy metabolism","volume":"162","author":"Yumnam","year":"2021","journal-title":"Free Radic. Biol. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1111462\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T10:58:07Z","timestamp":1681210687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1111462\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,3]]},"references-count":42,"alternative-id":["10.3389\/fphar.2023.1111462"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1111462","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,3]]},"article-number":"1111462"}}