{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:04:08Z","timestamp":1785769448535,"version":"3.56.0"},"reference-count":63,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver cancers are rising worldwide. Between molecular and epidemiological studies, a research gap has emerged which might be amenable to the technique of metabolomics. This review investigates the current understanding of liver cancer\u2019s trends, etiology and its correlates with existing literature for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatoblastoma (HB). Among additional factors, the literature reports dysfunction in the tricarboxylic acid metabolism, primarily for HB and HCC, and point mutations and signaling for CCA. All cases require further investigation of upstream and downstream events. All liver cancers reported dysfunction in the WNT\/\u03b2-catenin and P13K\/AKT\/mTOR pathways as well as changes in FGFR. Metabolites of IHD1, IDH2, miRNA, purine, Q10, lipids, phosphatidylcholine, phosphatidylethanolamine, acylcarnitine, 2-HG and propionyl-CoA emerged as crucial and there was an attempt to elucidate the WNT\/\u03b2-catenin and P13K\/AKT\/mTOR pathways metabolomically.<\/jats:p>","DOI":"10.3390\/ijms24032409","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T02:29:31Z","timestamp":1674700171000},"page":"2409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Primary Liver Cancers: Connecting the Dots of Cellular Studies and Epidemiology with Metabolomics"],"prefix":"10.3390","volume":"24","author":[{"given":"Shoma","family":"Berkemeyer","sequence":"first","affiliation":[{"name":"Faculty of Agricultural Sciences and Landscape Architecture, Osnabrueck University of Applied Sciences, Am Kruempel 31, 49090 Osnabrueck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","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 Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"047","DOI":"10.1055\/s-2006-939841","article-title":"Epidemiology of Primary and Secondary Liver Cancers","volume":"23","author":"Ananthakrishnan","year":"2006","journal-title":"Semin. Interv. Radiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Aguiar, T.F.M., Rivas, M.P., Costa, S., Maschietto, M., Rodrigues, T., de Barros, J.S., Barbosa, A.C., Valieris, R., Fernandes, G.R., and Bertola, D.R. (2020). Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00556"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.jhep.2014.08.009","article-title":"The genomic landscape of hepatoblastoma and their progenies with HCC-like features","volume":"61","author":"Trippel","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"417","DOI":"10.3748\/wjg.v22.i1.417","article-title":"Nuclear magnetic resonance based metabolomics and liver diseases: Recent advances and future clinical applications","volume":"22","author":"Amathieu","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1002\/pbc.25128","article-title":"Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: A report from the Children\u2019s Oncology Group","volume":"61","author":"Turcotte","year":"2014","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"028","DOI":"10.1055\/s-0040-1722645","article-title":"Molecular Mechanisms of Hepatoblastoma","volume":"41","author":"Zhang","year":"2021","journal-title":"Semin. Liver Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/cncr.20061","article-title":"Birth characteristics and hepatoblastoma risk in young children","volume":"100","author":"Reynolds","year":"2004","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.ccr.2008.11.002","article-title":"Hepatic stem-like phenotype and interplay of Wnt\/beta-catenin and Myc signaling in aggressive childhood liver cancer","volume":"14","author":"Cairo","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.jhep.2020.03.025","article-title":"Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications","volume":"73","author":"Torrens","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1016\/j.jcmgh.2021.08.020","article-title":"An Epigenetic Switch Between Differentiation and Proliferation in Hepatoblastoma","volume":"12","author":"Albrecht","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1002\/jimd.12143","article-title":"Liver neoplasms in methylmalonic aciduria: An emerging complication","volume":"42","author":"Forny","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00394-009-0012-3","article-title":"Regulation of expression of apolipoprotein A-I by selenium status in human liver hepatoblastoma cells","volume":"48","author":"Stahle","year":"2009","journal-title":"Eur. J. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1186\/s12885-015-1425-4","article-title":"Hyperemesis gravidarum and risk of cancer in offspring, a Scandinaivan registry-based nested case-control study","volume":"15","author":"Vandraas","year":"2015","journal-title":"BMC Cancer"},{"key":"ref_15","first-page":"557","article-title":"Consensus Statement. Chlolangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_16","first-page":"537","article-title":"Cholangiocarcinoma: Epidemiology, mechanisms of carcinogenesis and prevention","volume":"2","author":"Parkin","year":"1993","journal-title":"Cancer Epidemiol. Biomark. Prev"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.gcb.2010.01.008","article-title":"Cholangiocarcinoma: Descriptive epidemiology and risk factors","volume":"34","author":"Plummer","year":"2010","journal-title":"Gastroenterol. Clin. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1053\/j.gastro.2011.12.005","article-title":"Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors","volume":"142","author":"Andersen","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1038\/onc.2012.315","article-title":"Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas","volume":"32","author":"Wang","year":"2013","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1002\/hep.26890","article-title":"Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma","volume":"59","author":"Arai","year":"2014","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3727\/105221617X15088670121925","article-title":"Molecular mechansims driving cholangiocarcinoma invasiveness: An overview","volume":"18","author":"Brivio","year":"2018","journal-title":"Gene Expr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: 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_23","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/j.gastro.2016.11.048","article-title":"Liver cancer cell of origin, molecular class and effects on patient prognosis","volume":"152","author":"Sia","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2147\/JHC.S159805","article-title":"Combined hepatocellular cholangiocarcinoma (cHCC-CC): An update of genetics, molecular biology, and therapeutic interventions","volume":"6","author":"Stavraka","year":"2019","journal-title":"J Hepatocell. Carcinoma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ccell.2017.05.009","article-title":"Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma","volume":"32","author":"Chaisaingmongkol","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.3390\/cells9061370","article-title":"Biomarkers in hepatocellular carcinoma; diagnosis, prognosis and treatment response assessment","volume":"9","author":"Pinero","year":"2020","journal-title":"Cells"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, H.-Y., Nga, H., Tian, J., and Yi, H.-S. (2021). Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma. Cells, 10.","DOI":"10.3390\/cells10081901"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13046-021-02208-x","article-title":"Epigenetic regulation of ferroptosis via ETS1\/miR-23a-3p\/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma","volume":"41","author":"Lu","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Loong, J.H., Wong, T.-L., Tong, M., Sharma, R., Zhou, L., Ng, K.-Y., Yu, H.-J., Li, C.-H., Man, K., and Lo, C.-M. (2021). Glucose deprivation\u2013induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma. J. Clin. Investig., 131.","DOI":"10.1172\/JCI143377"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/s41467-021-27923-z","article-title":"RNF43\/ZNRF3 loss predisposes to hepatocellu-larcarcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state","volume":"13","author":"Belenguer","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nature11019","article-title":"ZNRF3 promotes Wnt receptor turnover in an R-spondinsensitive manner","volume":"485","author":"Hao","year":"2012","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1101\/gad.235473.113","article-title":"The R-spondin\/Lgr5\/Rnf43 module: Regulator of Wnt signal strength","volume":"28","author":"Peng","year":"2014","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/hep.32328","article-title":"The RSPO-LGR4\/5-ZNRF3\/RNF43 module in liver homeostasis, regeneration, and disease","volume":"76","author":"Annunziato","year":"2022","journal-title":"Hepatology."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ccr.2006.06.016","article-title":"Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment","volume":"10","author":"Budhu","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1084\/jem.20040912","article-title":"An anti-CD45RO\/RB monoclonal antibody modulates T cell responses via induction of apoptosis and gen-eration of regulatory T cells","volume":"201","author":"Gregori","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ni.2866","article-title":"Protein kinase C-eta controls CTLA-4-mediated regulatory T cell function","volume":"15","author":"Kong","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15129","DOI":"10.1038\/ncomms15129","article-title":"The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion","volume":"8","author":"Jiang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"169","DOI":"10.4049\/jimmunol.2001357","article-title":"Engineering cancer antigen-specific T cells to overcome the immunosuppressive effects of TGF-\u03b2","volume":"208","author":"Silk","year":"2022","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12935-022-02666-z","article-title":"Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: An updated overview","volume":"22","author":"Ali","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-018-0061-3","article-title":"Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women","volume":"24","author":"Hoyles","year":"2018","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/0006-2944(81)90026-0","article-title":"The specific inhibition of the pyruvate dehydrogenase complex from pig kidney by propionyl-CoA and iso-valeryl-Co-A","volume":"26","author":"Gregersen","year":"1981","journal-title":"Biochem. Med."},{"key":"ref_42","first-page":"905","article-title":"Effect of 2-methylcitrate on citrate metabolism: Implications for the man-agement of patients with propionic academia and methylmalonic aciduria","volume":"12","author":"Leznoff","year":"1975","journal-title":"Pediatr. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/hep.510310201","article-title":"Oxygen: Modulator of metabolic zonation and disease of the liver","volume":"31","author":"Jungermann","year":"2000","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1089\/ars.2008.2270","article-title":"Regulation of autophagy by reactive oxygen species (ROS): Implications for cancer pro-gression and treatment","volume":"11","author":"Azad","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/cr.2010.178","article-title":"Crosstalk of reactive oxygen species and NF-\u03baB signaling","volume":"21","author":"Morgan","year":"2011","journal-title":"Cell Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1177271918755391","DOI":"10.1177\/1177271918755391","article-title":"Reactive Oxygen Species: A Key Constituent in Cancer Survival","volume":"13","author":"Kumari","year":"2018","journal-title":"Biomark. Insights"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1111\/j.1471-4159.2006.04397.x","article-title":"Propionate increases neu-ronal histone acetylation, but is metabolized oxidatively by glia. Relevance for propionic academia","volume":"101","author":"Nguyen","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/j.1477-2574.2010.00185.x","article-title":"Metabolic profiling of bile in cholangiocarcinoma using in vitro magnetic resonance spectroscopy","volume":"12","author":"Sharif","year":"2010","journal-title":"Hpb"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bbamem.2017.04.006","article-title":"The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease","volume":"1859","author":"Kennelly","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA) Biomembr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1053\/j.gastro.2009.04.015","article-title":"ANXA8 Down-regulation by EGF-FOXO4 Signaling Is Involved in Cell Scattering and Tumor Metastasis of Cholangiocarcinoma","volume":"137","author":"Lee","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1021\/acs.jproteome.9b00185","article-title":"Metabolomic analysis of liver tissues for characterization of hepato-cellular carcinoma","volume":"18","author":"Ferrarini","year":"2019","journal-title":"J. Proteome. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1158\/0008-5472.CAN-15-3199","article-title":"Ac-etylcarnitine Is a Candidate Diagnostic and Prognostic Biomarker of Hepatocellular Carcinoma","volume":"76","author":"Lu","year":"2016","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1158\/0008-5472.CAN-20-3134","article-title":"DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer","volume":"81","author":"Lulli","year":"2021","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tibs.2016.09.009","article-title":"A New View into the Regulation of Purine Metabolism: The Purinosome","volume":"42","author":"Pedley","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5032","DOI":"10.18632\/oncotarget.23494","article-title":"Comparison of hepatic and serum lipid signatures in hepatocellular carcinoma patients leads to the discovery of diagnostic and prognostic biomarkers","volume":"9","author":"Lu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1158\/1078-0432.CCR-17-0853","article-title":"Deep Learning\u2013Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer","volume":"24","author":"Chaudhary","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.ccell.2017.11.011","article-title":"mTORC2 Promotes Tumorigenesis via Lipid Synthesis","volume":"32","author":"Guri","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.cmet.2018.12.020","article-title":"Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression","volume":"29","author":"Ericksen","year":"2019","journal-title":"Cell Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101760","DOI":"10.1016\/j.canep.2020.101760","article-title":"Epidemiology of liver metastases","volume":"67","author":"Horn","year":"2020","journal-title":"Cancer Epidemiol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ganesan, R., Yoon, S.J., and Suk, K.T. (2022). Microbiome and Metabolomics in Liver Cancer: Scientific Technology. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010537"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5971","DOI":"10.1158\/1078-0432.CCR-16-0460","article-title":"Role of the Microenvironment in Liver Metastasis: From Pre- to Prometastatic Niches","volume":"22","author":"Brodt","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.mehy.2009.12.034","article-title":"The straight line hypothesis elaborated: Case reference obesity, an argument for acidosis, oxidative stress, and disease conglomeration?","volume":"75","author":"Berkemeyer","year":"2010","journal-title":"Med. Hypotheses"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.mehy.2008.09.059","article-title":"Acid-base balance and weight gain: Are there crucial links via protein and organic acids in understanding obesity?","volume":"73","author":"Berkemeyer","year":"2009","journal-title":"Med. Hypotheses"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:15:52Z","timestamp":1760120152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,26]]},"references-count":63,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032409"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032409","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,26]]}}}