{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T23:32:08Z","timestamp":1788564728193,"version":"build-2803163510"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"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. Mol. Biosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is a syn-drome with a high short-term mortality rate, and its prognosis is critical in clinical management. This study aimed to investigate the clinical significance of glutathione peroxidase 4 (GPX4) in the occurrence and development of HBV-ACLF and its prognostic value for 90-day mortality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression levels of GPX4, oxidative stress-related molecules and inflammatory cytokines in serum or peripheral blood mononuclear cells (PBMCs) of 289 participants were determined by RT-qPCR or ELISA, and the methylation level of GPX4 promoter in PBMCs was determined by MethyLight.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expression levels of GPX4 in the PBMCs and serum of HBV-ACLF patients were lower than those in non-HBV-associated acute-on-chronic liver failure (non-HBV ACLF) patients, patients with chronic hepatitis B (CHB) and healthy control (HC) individuals, while the methylation level of the <jats:italic>GPX4<\/jats:italic> promoter was greater. In HBV-ACLF patients, the methylation level of the <jats:italic>GPX4<\/jats:italic> promoter is correlated with oxidative stress, inflammation-related molecules, and some clinicopathological indicators. The methylation level of the <jats:italic>GPX4<\/jats:italic> promoter was identified as an independent risk factor for 90-day mortality in HBV-ACLF patients and yielded a larger area under the receiver operating characteristic curve (AUROC) than the model for end-stage liver disease (MELD) score in predicting 90-day mortality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The GPX4 promoter methylation level has promising potential as a predictor of 90-day mortality in patients with HBV-ACLF.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmolb.2024.1421597","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T04:54:38Z","timestamp":1721883278000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Hypermethylation of the glutathione peroxidase 4 promoter predicts poor prognosis in patients with hepatitis B virus-associated acute-on-chronic liver failure"],"prefix":"10.3389","volume":"11","author":[{"given":"Xing","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Yu","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chen","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.cbpa.2017.06.002","article-title":"Lipid homeostasis and regulated cell death","volume":"39","author":"Agmon","year":"2017","journal-title":"Curr. Opin. Chem. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1056\/NEJMra1914900","article-title":"Acute-on-Chronic liver failure","volume":"382","author":"Arroyo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.freeradbiomed.2003.10.027","article-title":"Inhibition of basal and interleukin-1-induced VCAM-1 expression by phospholipid hydroperoxide glutathione peroxidase and 15-lipoxygenase in rabbit aortic smooth muscle cells","volume":"36","author":"Banning","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"39","DOI":"10.3233\/cbm-2010-0146","article-title":"Impaired expression of glutathione peroxidase-4 gene in peripheral blood mononuclear cells: a biomarker of increased breast cancer risk","volume":"7","author":"Bermano","year":"2010","journal-title":"Cancer Biomark."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1016\/s0140-6736(15)00309-8","article-title":"Acute-on-chronic liver failure","volume":"386","author":"Bernal","year":"2015","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.redox.2016.05.003","article-title":"Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration","volume":"9","author":"Carlson","year":"2016","journal-title":"Redox Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e20210518","DOI":"10.1084\/jem.20210518","article-title":"Ferroptosis in infection, inflammation, and immunity","volume":"218","author":"Chen","year":"2021","journal-title":"J. Exp. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"S49","DOI":"10.1016\/j.jhep.2021.01.002","article-title":"Pathophysiology of decompensated cirrhosis: portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction","volume":"75","author":"Engelmann","year":"2021","journal-title":"J. Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1620\/tjem.238.57","article-title":"Methylation of the glutathione-S-transferase P1 gene promoter is associated with oxidative stress in patients with chronic hepatitis B","volume":"238","author":"Fan","year":"2016","journal-title":"Tohoku J. Exp. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1111\/apt.13271","article-title":"Aberrant GSTP1 promoter methylation predicts short-term prognosis in acute-on-chronic hepatitis B liver failure","volume":"42","author":"Gao","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1002\/hep.30947","article-title":"HBx protein contributes to liver carcinogenesis by H3K4me3 modification through stabilizing WD repeat domain 5 protein","volume":"71","author":"Gao","year":"2020","journal-title":"Hepatology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/s41575-023-00760-9","article-title":"Global burden of hepatitis B virus: current status, missed opportunities and a call for action","volume":"20","author":"Hsu","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/s41590-020-0699-0","article-title":"Redox homeostasis maintained by GPX4 facilitates STING activation","volume":"21","author":"Jia","year":"2020","journal-title":"Nat. Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: islands, start sites, gene bodies and beyond","volume":"13","author":"Jones","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.chom.2018.05.009","article-title":"Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis","volume":"24","author":"Kang","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.1172\/jci91075","article-title":"TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury","volume":"127","author":"Lan","year":"2017","journal-title":"J. Clin. Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"3691","DOI":"10.1016\/j.molcel.2021.08.018","article-title":"Redox metabolism: ROS as specific molecular regulators of cell signaling and function","volume":"81","author":"Lennicke","year":"2021","journal-title":"Mol. Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.3389\/fphar.2018.01120","article-title":"Activation of glutathione peroxidase 4 as a novel anti-inflammatory strategy","volume":"9","author":"Li","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s13148-023-01495-9","article-title":"SOCS1 methylation level is associated with prognosis in patients with acute-on-chronic hepatitis B liver failure","volume":"15","author":"Li","year":"2023","journal-title":"Clin. Epigenetics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1136\/gutjnl-2020-323395","article-title":"PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF","volume":"71","author":"Li","year":"2022","journal-title":"Gut"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1093\/bioinformatics\/18.11.1427","article-title":"MethPrimer: designing primers for methylation PCRs","volume":"18","author":"Li","year":"2002","journal-title":"Bioinformatics"},{"key":"B23","doi-asserted-by":"publisher","first-page":"20176","DOI":"10.1038\/s41598-020-77235-3","article-title":"A prediction model for outcome in patients with HBV-ACLF based on predisposition, injury, response and organ failure","volume":"10","author":"Liu","year":"2020","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12929-021-00762-2","article-title":"HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression","volume":"28","author":"Liu","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.jcmgh.2021.09.008","article-title":"Trypsin-mediated sensitization to ferroptosis increases the severity of pancreatitis in mice","volume":"13","author":"Liu","year":"2022","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1053\/he.2000.5852","article-title":"A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts","volume":"31","author":"Malinchoc","year":"2000","journal-title":"Hepatology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1038\/s41467-020-15646-6","article-title":"Dietary lipids fuel GPX4-restricted enteritis resembling Crohn\u2019s disease","volume":"11","author":"Mayr","year":"2020","journal-title":"Nat. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"849","DOI":"10.2147\/tcrm.S272463","article-title":"Serum lactate level predicts short-term and long-term mortality of HBV-ACLF patients: a prospective study","volume":"16","author":"Nie","year":"2020","journal-title":"Ther. Clin. Risk Manag."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15733","article-title":"Mechanisms and treatment approaches for ACLF","author":"Piano","year":"2023","journal-title":"Liver Int."},{"key":"B30","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/nrgastro.2015.219","article-title":"Acute-on-chronic liver failure: terminology, mechanisms and management","volume":"13","author":"Sarin","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s12072-019-09946-3","article-title":"Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update","volume":"13","author":"Sarin","year":"","journal-title":"Hepatol. Int."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1038\/jid.2013.52","article-title":"Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2","volume":"133","author":"Sengupta","year":"2013","journal-title":"J. Invest Dermatol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"5178","DOI":"10.1002\/cam4.1778","article-title":"Distinctive pattern of AHNAK methylation level in peripheral blood mononuclear cells and the association with HBV-related liver diseases","volume":"7","author":"Sun","year":"2018","journal-title":"Cancer Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1091103","DOI":"10.3389\/fimmu.2022.1091103","article-title":"Diagnostic and prognostic value of STAP1 and AHNAK methylation in peripheral blood immune cells for HBV-related hepatopathy","volume":"13","author":"Sun","year":"2022","journal-title":"Front. Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1002\/hep.29800","article-title":"Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance","volume":"67","author":"Terrault","year":"2018","journal-title":"Hepatology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.1016\/j.apsb.2022.02.003","article-title":"Targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease","volume":"12","author":"Tong","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"B37","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.redox.2016.01.010","article-title":"Redox homeostasis: the Golden Mean of healthy living","volume":"8","author":"Ursini","year":"2016","journal-title":"Redox Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e24075","DOI":"10.1097\/md.0000000000024075","article-title":"Peripheral T lymphocytes predict the severity and prognosis in patients with HBV-related acute-on-chronic liver failure","volume":"100","author":"Wang","year":"2021","journal-title":"Med. Baltim."},{"key":"B39","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41419-021-03718-4","article-title":"GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2\/GPX4 axis","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3390\/biomedicines10040891","article-title":"The selenoprotein glutathione peroxidase 4: from molecular mechanisms to novel therapeutic opportunities","volume":"10","author":"Weaver","year":"2022","journal-title":"Biomedicines"},{"key":"B41","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.virol.2023.04.009","article-title":"Hypomethylation of Tumor necrosis factor-like cytokine 1A(TL1A) and its decoy receptor 3 expressive level increase has diagnostic value in HBV-associated cirrhosis","volume":"585","author":"Wei","year":"2023","journal-title":"Virology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1080\/15548627.2023.2218764","article-title":"GPX4 in cell death, autophagy, and disease","volume":"19","author":"Xie","year":"2023","journal-title":"Autophagy"},{"key":"B43","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s12916-023-02878-8","article-title":"Oxidative stress gene expression, DNA methylation, and gut microbiota interaction trigger Crohn\u2019s disease: a multi-omics Mendelian randomization study","volume":"21","author":"Xu","year":"2023","journal-title":"BMC Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"514","DOI":"10.14218\/jcth.2021.00028","article-title":"Novel prognostic models for predicting the 180-day outcome for patients with hepatitis-B virus-related acute-on-chronic liver failure","volume":"9","author":"Xue","year":"2021","journal-title":"J. Clin. Transl. Hepatol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1007\/s12072-022-10351-6","article-title":"Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma","volume":"16","author":"Yang","year":"2022","journal-title":"Hepatol. Int."},{"key":"B46","doi-asserted-by":"publisher","first-page":"865689","DOI":"10.3389\/fphar.2022.865689","article-title":"Maresin1 protect against ferroptosis-induced liver injury through ROS inhibition and Nrf2\/HO-1\/GPX4 activation","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1038\/s41418-022-00939-8","article-title":"EBV infection-induced GPX4 promotes chemoresistance and tumor progression in nasopharyngeal carcinoma","volume":"29","author":"Yuan","year":"2022","journal-title":"Cell Death Differ."},{"key":"B49","doi-asserted-by":"publisher","first-page":"100176","DOI":"10.1016\/j.jhepr.2020.100176","article-title":"Acute-on-chronic liver failure: definitions, pathophysiology and principles of treatment","volume":"3","author":"Zaccherini","year":"2021","journal-title":"JHEP Rep."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2024.1421597\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T04:54:41Z","timestamp":1721883281000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2024.1421597\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,25]]},"references-count":49,"alternative-id":["10.3389\/fmolb.2024.1421597"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2024.1421597","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,25]]},"article-number":"1421597"}}