{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T07:32:58Z","timestamp":1767598378719,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T00:00:00Z","timestamp":1737417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission Horizon 2020 Framework Program","doi-asserted-by":"publisher","award":["856871"],"award-info":[{"award-number":["856871"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Introduction: The most common liver disease is nonalcoholic fatty liver disease, characterized by an intrahepatic accumulation of lipids that most often accompanies obesity. Fatty liver can evolve, in the presence of oxidative stress and inflammation, into disabling and deadly liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma (CC). Old age seems to favor HCC and CC, in agreement with the inflammaging theory, according to which aging accrues inflammation. Cancer, in general, is an age-related disease, as incidence and mortality for most types of cancer increase with age. However, how molecular drivers in tumors differ or are mutated more frequently among patients of different ages remains scarcely investigated. A recent integrative analysis of the age-associated multi-omic landscape across cancers and healthy tissues demonstrated that age-related gene expression changes are linked to numerous biological processes. HCC and CC have among the lowest five-year survival estimates due to their aggressive progression. Materials and methods: In this study, we extracted top gene candidates from the above-mentioned pan-analyses (i.e., B2M, C1qA, SUCLG1) and tested by qPCR their expression and their correlation with disease progression in 48 tissue samples covering liver disease stages (fatty liver, hepatitis, cirrhosis, HCC and CC) and normal tissues. Results: Here, we report a significant downregulation in the expression of the age-associated gene SUCLG1 during the progression of liver disease toward HCC and CC, which also associates with poor patient survival. Conclusion: SUCGL1, a mitochondrial enzyme gene that catalyzes the conversion of succinyl CoA to succinate, might be therapeutically targeted for the development and progression of age-associated liver cancers with low survival rates.<\/jats:p>","DOI":"10.3390\/cancers17030339","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T04:19:51Z","timestamp":1737433191000},"page":"339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Downregulation of Aging-Associated Gene SUCLG1 Marks the Aggressiveness of Liver Disease"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8141-2482","authenticated-orcid":false,"given":"Desislava K.","family":"Tsoneva","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Medical University of Varna, 9002 Varna, Bulgaria"},{"name":"Department of Stem Cell Biology and Transplantology, Research Institute of the Medical University of Varna, 9002 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Napoli","sequence":"additional","affiliation":[{"name":"Bioinformatics Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 S. Giovanni Rotondo, FG, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariya","family":"Teneva","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical University of Varna, 9002 Varna, Bulgaria"},{"name":"Department of Stem Cell Biology and Transplantology, Research Institute of the Medical University of Varna, 9002 Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-8533","authenticated-orcid":false,"given":"Tommaso","family":"Mazza","sequence":"additional","affiliation":[{"name":"Bioinformatics Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 S. Giovanni Rotondo, FG, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manlio","family":"Vinciguerra","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Transplantology, Research Institute of the Medical University of Varna, 9002 Varna, Bulgaria"},{"name":"Faculty of Science, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1146\/annurev-physiol-030212-183653","article-title":"Aging, Cellular Senescence, and Cancer","volume":"75","author":"Campisi","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nrc3497","article-title":"How Ageing Processes Influence Cancer","volume":"13","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.exger.2017.10.024","article-title":"Age and Immunity: What Is \u201cImmunosenescence\u201d?","volume":"105","author":"Pawelec","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The Hallmarks of Aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1016\/j.febslet.2010.05.026","article-title":"Telomeres and Telomerase in Normal and Cancer Stem Cells","volume":"584","author":"Shay","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Baylin, S.B., and Jones, P.A. (2016). Epigenetic Determinants of Cancer. Cold Spring Harb. Perspect. Biol., 8.","DOI":"10.1101\/cshperspect.a019505"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA Methylation-Based Biomarkers and the Epigenetic Clock Theory of Ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nature05985","article-title":"The Common Biology of Cancer and Ageing","volume":"448","author":"Finkel","year":"2007","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1083\/jcb.201708099","article-title":"Stem Cells: Aging and Transcriptional Fingerprints","volume":"217","author":"Keyes","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A New Immune\u2013Metabolic Viewpoint for Age-Related Diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111939","DOI":"10.1016\/j.mad.2024.111939","article-title":"Inflammaging Score as a Potential Prognostic Tool for Cancer: A Population-Based Cohort Study","volume":"219","author":"Xie","year":"2024","journal-title":"Mech. Ageing Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1177\/107327480701400104","article-title":"Biology of Aging and Cancer","volume":"14","author":"Anisimov","year":"2007","journal-title":"Cancer Control"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1111\/acel.12128","article-title":"Liver Diseases and Aging: Friends or Foes?","volume":"12","author":"Sheedfar","year":"2013","journal-title":"Aging Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/hep.26212","article-title":"Old Age and Steatohepatitis: A Dangerous Liaison?","volume":"58","author":"Vinciguerra","year":"2013","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of Liver Diseases in the World","volume":"70","author":"Asrani","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular Carcinoma","volume":"380","author":"Villanueva","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Cholangiocarcinoma: Current Knowledge and Future Perspectives Consensus Statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)","volume":"13","author":"Banales","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"110005","DOI":"10.1016\/j.celrep.2021.110005","article-title":"Genomic and Molecular Features Distinguish Young Adult Cancer from Later-Onset Cancer","volume":"37","author":"Lee","year":"2021","journal-title":"Cell Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"110100","DOI":"10.1016\/j.celrep.2021.110100","article-title":"Pan-Cancer Analysis Reveals Molecular Patterns Associated with Age","volume":"37","author":"Shah","year":"2021","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.trecan.2022.06.007","article-title":"Age-Associated Differences in the Cancer Molecular Landscape","volume":"8","author":"Chatsirisupachai","year":"2022","journal-title":"Trends Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.18632\/aging.202648","article-title":"Ageing Transcriptome Meta-Analysis Reveals Similarities and Differences between Key Mammalian Tissues","volume":"13","author":"Palmer","year":"2021","journal-title":"Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1038\/s41467-021-22560-y","article-title":"An Integrative Analysis of the Age-Associated Multi-Omic Landscape across Cancers","volume":"12","author":"Chatsirisupachai","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.21105\/joss.01317","article-title":"Lifelines: Survival Analysis in Python","volume":"4","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1158\/0008-5472.CAN-15-1336","article-title":"DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression","volume":"76","author":"Borghesan","year":"2016","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41416-021-01569-6","article-title":"Cancer-Associated Fibroblast Senescence and Its Relation with Tumour-Infiltrating Lymphocytes and PD-L1 Expressions in Intrahepatic Cholangiocarcinoma","volume":"126","author":"Lan","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1016\/j.jhep.2022.07.029","article-title":"Combined Hepatocellular-Cholangiocarcinoma Derives from Liver Progenitor Cells and Depends on Senescence and IL-6 Trans-Signaling","volume":"77","author":"Rosenberg","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5174","DOI":"10.1016\/j.csbj.2023.09.020","article-title":"HELLS Modulates the Stemness of Intrahepatic Cholangiocarcinoma through Promoting Senescence-Associated Secretory Phenotype","volume":"21","author":"Du","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kovacovicova, K., Skolnaja, M., Heinmaa, M., Mistrik, M., Pata, P., Pata, I., Bartek, J., and Vinciguerra, M. (2018). Senolytic Cocktail Dasatinib+Quercetin (D+Q) Does Not Enhance the Efficacy of Senescence-Inducing Chemotherapy in Liver Cancer. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00459"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12964-021-00731-0","article-title":"Mild Exacerbation of Obesity- and Age-Dependent Liver Disease Progression by Senolytic Cocktail Dasatinib + Quercetin","volume":"19","author":"Raffaele","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s13311-013-0177-6","article-title":"Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options","volume":"10","author":"Scaglia","year":"2013","journal-title":"Neurotherapeutics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1038\/s44318-024-00101-9","article-title":"SUCLG1 Restricts POLRMT Succinylation to Enhance Mitochondrial Biogenesis and Leukemia Progression","volume":"43","author":"Yan","year":"2024","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6609","DOI":"10.3390\/curroncol30070485","article-title":"Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options","volume":"30","author":"Pourbaghi","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pant, K., Richard, S., Peixoto, E., and Gradilone, S.A. (2020). Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00113"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.14336\/AD.2022.0318","article-title":"Non-Alcoholic Fatty Liver Disease and Liver Fibrosis during Aging","volume":"13","author":"Li","year":"2022","journal-title":"Aging Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s12974-024-03284-4","article-title":"Up-Regulated Succinylation Modifications Induce a Senescence Phenotype in Microglia by Altering Mitochondrial Energy Metabolism","volume":"21","author":"Zhao","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1002\/1878-0261.13261","article-title":"Metabolic Reprogramming: A Bridge between Aging and Tumorigenesis","volume":"16","author":"Drapela","year":"2022","journal-title":"Mol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101580","DOI":"10.1016\/j.aohep.2024.101580","article-title":"Is the Liver Resilient to the Process of Ageing?","volume":"30","author":"Chatterjee","year":"2025","journal-title":"Ann. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1186\/s12935-020-01405-6","article-title":"Identifying the Novel Key Genes in Renal Cell Carcinoma by Bioinformatics Analysis and Cell Experiments","volume":"20","author":"Chen","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/s41467-018-03573-6","article-title":"Integrative Proteomics in Prostate Cancer Uncovers Robustness against Genomic and Transcriptomic Aberrations during Disease Progression","volume":"9","author":"Latonen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e148438","DOI":"10.1172\/jci.insight.148438","article-title":"The TGF-\u03b2\/HDAC7 Axis Suppresses TCA Cycle Metabolism in Renal Cancer","volume":"6","author":"Nam","year":"2021","journal-title":"JCI Insight"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.neuropharm.2012.05.012","article-title":"Energy Depletion in Seizures: Anaplerosis as a Strategy for Future Therapies","volume":"69","author":"Kovac","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ram\u00f3n, J., Vila-Juli\u00e0, F., Molina-Granada, D., Molina-Berenguer, M., Meli\u00e0, M.J., Garc\u00eda-Arum\u00ed, E., Torres-Torronteras, J., C\u00e1mara, Y., and Mart\u00ed, R. (2021). Therapy Prospects for Mitochondrial DNA Maintenance Disorders. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126447"},{"key":"ref_43","first-page":"CD013731","article-title":"Gene Therapy for People with Hepatocellular Carcinoma","volume":"2024","author":"Naing","year":"2024","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5702","DOI":"10.1111\/jcmm.17507","article-title":"Protein Succinylation Associated with the Progress of Hepatocellular Carcinoma","volume":"26","author":"Bai","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1074\/mcp.M111.015875","article-title":"Lysine Succinylation and Lysine Malonylation in Histones","volume":"11","author":"Xie","year":"2012","journal-title":"Mol. Cell. Proteom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nchembio.495","article-title":"Identification of Lysine Succinylation as a New Post-Translational Modification","volume":"7","author":"Zhang","year":"2011","journal-title":"Nat. Chem. Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/339\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:32:37Z","timestamp":1759919557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,21]]},"references-count":46,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cancers17030339"],"URL":"https:\/\/doi.org\/10.3390\/cancers17030339","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2025,1,21]]}}}