{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:43:55Z","timestamp":1793054635236,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"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><jats:title>Introduction<\/jats:title><jats:p>Non-alcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease, still lacks effective therapeutic targets today. Ferroptosis, a type of cell death characterized by lipid peroxidation, has been linked to NAFLD in certain preclinical trials, yet the exact molecular mechanism remains unclear. Thus, we analyzed the relationship between ferroptosis genes and NAFLD using high-throughput data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We utilized a total of 282 samples from five datasets, including two mouse ones, one human one, one single nucleus dataset and one single cell dataset from Gene Expression Omnibus (GEO), as the data basis of our study. To filter robust treatment targets, we employed four machine learning methods (LASSO, SVM, RF and Boruta). In addition, we used an unsupervised consensus clustering algorithm to establish a typing scheme for NAFLD based on the expression of ferroptosis related genes (FRGs). Our study is also the first to investigate the dynamics of FRGs throughout the disease process by time series analysis. Finally, we validated the relationship between core gene and ferroptosis by <jats:italic>in vitro<\/jats:italic> experiments on HepG2 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We discovered ANXA2 as a central focus in NAFLD and indicated its potential to boost ferroptosis in HepG2 cells. Additionally, based on the results obtained from time series analysis, ANXA2 was observed to significantly define the disease course of NAFLD. Our results demonstrate that implementing a ferroptosis-based staging method may hold promise for the diagnosis and treatment of NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest that ANXA2 may be a useful biomarker for the diagnosis and characterization of NAFLD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1303426","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T09:15:10Z","timestamp":1702977310000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Machine learning identifies ferroptosis-related gene ANXA2 as potential diagnostic biomarkers for NAFLD"],"prefix":"10.3389","volume":"14","author":[{"given":"Jingtong","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuexuan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyan","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianxiang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of nafld and nash: trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0014-9","article-title":"Noninvasive biomarkers in nafld and nash - current progress and future promise","volume":"15","author":"Wong","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27406","article-title":"The global burden of liver disease: the major impact of China","volume":"60","author":"Wang","year":"2014","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/nu14173459","article-title":"Berberine in non-alcoholic fatty liver disease-a review","volume":"14","author":"Koperska","year":"2022","journal-title":"Nutrients"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-021-05442-2","article-title":"Liver-targeting drugs and their effect on blood glucose and hepatic lipids","volume":"64","author":"Gastaldelli","year":"2021","journal-title":"Diabetologia"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052350","article-title":"Treatments for NAFLD: State of art","volume":"22","author":"Mantovani","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i2.475","article-title":"Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"20","author":"Sumida","year":"2014","journal-title":"World J Gastroenterol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10020174","article-title":"Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: implications for prevention and therapy","volume":"10","author":"Arroyave-Ospina","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-021-02610-8","article-title":"Nonalcoholic steatohepatitis modifies serum iron-related variables in patients with morbid obesity","volume":"199","author":"Hern\u00e1ndez-Aguilera","year":"2021","journal-title":"Biol Trace Elem Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24038","article-title":"Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease","volume":"53","author":"Nelson","year":"2011","journal-title":"Hepatology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-022-01010-5","article-title":"Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of panoptosis","volume":"44","author":"Tong","year":"2023","journal-title":"Acta Pharmacol Sin"},{"key":"B14","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.freeradbiomed.2021.08.232","article-title":"Mitochondrial dysfunction in mouse livers depleted of iron chaperone pcbp1","volume":"175","author":"Jadhav","year":"2021","journal-title":"Free Radic Biol Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl887","article-title":"Ncbi geo: mining tens of millions of expression profiles\u2013database and tools update","volume":"35","author":"Barrett","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"Wgcna: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1131","article-title":"String V11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1529","article-title":"Genome-wide association study of lean nonalcoholic fatty liver disease suggests human leukocyte antigen as a novel candidate locus","volume":"4","author":"Yoshida","year":"2020","journal-title":"Hepatol Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-014-3688-2","article-title":"Hla dqb1 alleles are related with nonalcoholic fatty liver disease","volume":"41","author":"Doganay","year":"2014","journal-title":"Mol Biol Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.704704","article-title":"Comprehensive analysis of nafld and the therapeutic target identified","volume":"9","author":"Wen","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1186\/s12967-022-03692-1","article-title":"The P-stat3\/anxa2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis","volume":"20","author":"Feng","year":"2022","journal-title":"J Transl Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-010-9192-4","article-title":"Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration","volume":"4","author":"Chen","year":"2010","journal-title":"Hepatol Int"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90200-3","article-title":"Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a lewis lung carcinoma","volume":"79","author":"O'Reilly","year":"1994","journal-title":"Cell"},{"key":"B26","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.toxlet.2022.04.004","article-title":"The mouse anxa6\/mir-9-5p\/anxa2 axis modulates tgf-\u03b21-induced mouse hepatic stellate cell (Mhsc) activation and ccl(4)-caused liver fibrosis","volume":"362","author":"Liao","year":"2022","journal-title":"Toxicol Lett"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2022.166413","article-title":"The annexin A2-notch regulatory loop in hepatocytes promotes liver fibrosis in nafld by increasing osteopontin expression","volume":"1868","author":"Wang","year":"2022","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B28","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/s41419-019-1678-y","article-title":"Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis","volume":"10","author":"Tsurusaki","year":"2019","journal-title":"Cell Death Dis"},{"key":"B29","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.ajpath.2019.09.011","article-title":"Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice","volume":"190","author":"Qi","year":"2020","journal-title":"Am J Pathol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9111660","article-title":"Role of ferroptosis in non-alcoholic fatty liver disease and its implications for therapeutic strategies","volume":"9","author":"Zhang","year":"2021","journal-title":"Biomedicines"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/bs.vh.2016.04.011","article-title":"Thymosin beta 4 is a potential regulator of hepatic stellate cells","volume":"102","author":"Kim","year":"2016","journal-title":"Vitam Horm"},{"key":"B32","doi-asserted-by":"publisher","first-page":"661","DOI":"10.21037\/atm-21-471","article-title":"Eno3 promoted the progression of nash by negatively regulating ferroptosis via elevation of gpx4 expression and lipid accumulation","volume":"9","author":"Lu","year":"2021","journal-title":"Ann Transl Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcq170","article-title":"Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling\u2013a propensity score-adjusted observational study","volume":"104","author":"Valenti","year":"2011","journal-title":"Qjm"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2020.109824","article-title":"Ferroptosis mediated by the interaction between mfn2 and ire\u03b1 Promotes arsenic-induced nonalcoholic steatohepatitis","volume":"188","author":"Wei","year":"2020","journal-title":"Environ Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14428","article-title":"Targeting ferroptosis alleviates methionine-choline deficient (Mcd)-diet induced nash by suppressing liver lipotoxicity","volume":"40","author":"Li","year":"2020","journal-title":"Liver Int"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-023-01732-0","article-title":"The combination of machine learning and untargeted metabolomics identifies the lipid metabolism -related gene ch25h as a potential biomarker in asthma","volume":"72","author":"Ding","year":"2023","journal-title":"Inflamm Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-319019","article-title":"S100a11\/anxa2 belongs to a tumour suppressor\/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development","volume":"69","author":"Sobolewski","year":"2020","journal-title":"Gut"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e1005743","DOI":"10.1371\/journal.ppat.1005743","article-title":"Annexin A2 modulates ros and impacts inflammatory response via il-17 signaling in polymicrobial sepsis mice","volume":"12","author":"He","year":"2016","journal-title":"PloS Pathog"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11040492","article-title":"Annexin A2 regulates akt upon H2O2-dependent signaling activation in cancer cells","volume":"11","author":"Castaldo","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.12.007","article-title":"Celastrol induces ferroptosis in activated hscs to ameliorate hepatic fibrosis via targeting peroxiredoxins and ho-1","volume":"12","author":"Luo","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"B41","doi-asserted-by":"publisher","first-page":"389","DOI":"10.2337\/db22-0553","article-title":"Isorhapontigenin attenuates cardiac microvascular injury in diabetes via the inhibition of mitochondria-associated ferroptosis through prdx2-mfn2-acsl4 pathways","volume":"72","author":"Chen","year":"2023","journal-title":"Diabetes"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7150\/thno.44297","article-title":"Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with tlr4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder","volume":"10","author":"Hu","year":"2020","journal-title":"Theranostics"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.10.016","article-title":"Inhibition of egfr attenuates fibrosis and stellate cell activation in diet-induced model of nonalcoholic fatty liver disease","volume":"1864","author":"Liang","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1097\/00042737-200107000-00004","article-title":"Cytokines in the liver","volume":"13","author":"Ramadori","year":"2001","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101634","article-title":"Annexin A5 regulates hepatic macrophage polarization via directly targeting pkm2 and ameliorates nash","volume":"36","author":"Xu","year":"2020","journal-title":"Redox Biol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12010120","article-title":"The role of oxidative inactivation of phosphatase pten and tcptp in fatty liver disease","volume":"12","author":"Nguyen Huu","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.lfs.2018.10.051","article-title":"P53 as a double-edged sword in the progression of non-alcoholic fatty liver disease","volume":"215","author":"Yan","year":"2018","journal-title":"Life Sci"},{"key":"B48","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.ejphar.2018.08.040","article-title":"(Ssnb) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, tgf-beta signaling and focal adhesion that is tlr4 dependent","volume":"841","author":"Dattaroy","year":"2018","journal-title":"Eur J Pharmacol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00259.2015","article-title":"Sparstolonin B attenuates early liver inflammation in experimental nash by modulating tlr4 trafficking in lipid rafts via nadph oxidase activation","volume":"310","author":"Dattaroy","year":"2016","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2023.159287","article-title":"Zeaxanthin prevents ferroptosis by promoting mitochondrial function and inhibiting the P53 pathway in free fatty acid-induced hepg2 cells","volume":"1868","author":"Liu","year":"2023","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1303426\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T09:15:13Z","timestamp":1702977313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1303426\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,19]]},"references-count":50,"alternative-id":["10.3389\/fendo.2023.1303426"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1303426","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,19]]},"article-number":"1303426"}}