{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:28:03Z","timestamp":1789417683711,"version":"build-2803163510"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004423","name":"World Health Organization","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004423","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:p>Substantial attention has been paid to the various effects of metformin on liver diseases; the liver is the targeted organ where metformin exerts its antihyperglycemic properties. In non-alcoholic fatty liver disease (NAFLD), studies have shown that metformin affects the ATP\/AMP ratio to activate AMPK, subsequently governing lipid metabolism. The latest research showed that low-dose metformin targets the lysosomal AMPK pathway to decrease hepatic triglyceride levels through the PEN2-ATP6AP1 axis in an AMP-independent manner. Metformin regulates caspase-3, eukaryotic initiation factor-2a (eIF2a), and insulin receptor substrate-1 (IRS-1) in palmitate-exposed HepG2 cells, alleviating endoplasmic reticulum (ER) stress. Recent observations highlighted the critical association with intestinal flora, as confirmed by the finding that metformin decreased the relative abundance of <jats:italic>Bacteroides fragilis<\/jats:italic> while increasing <jats:italic>Akkermansia muciniphila<\/jats:italic> and <jats:italic>Bifidobacterium bifidum<\/jats:italic>. The suppression of intestinal farnesoid X receptor (FXR) and the elevation of short-chain fatty acids resulted in the upregulation of tight junction protein and the alleviation of hepatic inflammation induced by lipopolysaccharide (LPS). Additionally, metformin delayed the progression of cirrhosis by regulating the activation and proliferation of hepatic stellate cells (HSCs) via the TGF-\u03b21\/Smad3 and succinate-GPR91 pathways. In hepatocellular carcinoma (HCC), metformin impeded the cell cycle and enhanced the curative effect of antitumor medications. Moreover, metformin protects against chemical-induced and drug-induced liver injury (DILI) against hepatotoxic drugs. These findings suggest that metformin may have pharmacological efficacy against liver diseases.<\/jats:p>","DOI":"10.3389\/fnut.2023.1327814","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T14:57:36Z","timestamp":1702565856000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Metformin: update on mechanisms of action on liver diseases"],"prefix":"10.3389","volume":"10","author":[{"given":"Gaoyi","family":"Ruan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangquan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dibang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changlong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"553","DOI":"10.2337\/diacare.12.8.553","article-title":"Traditional plant medicines as treatments for diabetes","volume":"12","author":"Bailey","year":"1989","journal-title":"Diabetes Care"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: historical overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"813","DOI":"10.7326\/M20-2470","article-title":"Pharmacologic approaches to glycemic treatment of type 2 diabetes: synopsis of the 2020 American Diabetes Association's standards of medical Care in Diabetes Clinical Guideline","volume":"173","author":"Doyle-Delgado","year":"2020","journal-title":"Ann Intern Med"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"306","DOI":"10.2337\/db07-0381","article-title":"Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP","volume":"57","author":"Kim","year":"2008","journal-title":"Diabetes"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/nature07349","article-title":"A fasting inducible switch modulates gluconeogenesis via activator\/coactivator exchange","volume":"456","author":"Liu","year":"2008","journal-title":"Nature"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.cmet.2014.06.014","article-title":"The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism","volume":"20","author":"Zhang","year":"2014","journal-title":"Cell Metab"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.cmet.2016.09.003","article-title":"Metformin activates AMPK through the lysosomal pathway","volume":"24","author":"Zhang","year":"2016","journal-title":"Cell Metab"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41586-022-04431-8","article-title":"Low-dose metformin targets the lysosomal AMPK pathway through PEN2","volume":"603","author":"Ma","year":"2022","journal-title":"Nature"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1586\/17474124.2014.894880","article-title":"Metformin in the treatment of non-alcoholic fatty liver disease: safety, efficacy and mechanism","volume":"8","author":"Rouabhia","year":"2014","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2649","DOI":"10.1016\/j.bbrc.2017.12.143","article-title":"Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition","volume":"495","author":"Nguyen","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s10552-018-1058-4","article-title":"Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer","volume":"29","author":"Murff","year":"2018","journal-title":"Cancer Causes Control"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jhep.2015.02.008","article-title":"Metformin ameliorates acetaminophen hepatotoxicity via Gadd45\u03b2-dependent regulation of JNK signaling in mice","volume":"63","author":"Kim","year":"2015","journal-title":"J Hepatol"},{"key":"ref13","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":"Hepatol Baltimore"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","article-title":"Current and future pharmacological therapies for NAFLD\/NASH","volume":"53","author":"Sumida","year":"2018","journal-title":"J Gastroenterol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1056\/NEJMra011775","article-title":"Nonalcoholic fatty liver disease","volume":"346","author":"Angulo","year":"2002","journal-title":"N Engl J Med"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1053\/jhep.2003.50161","article-title":"Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome","volume":"37","author":"Marchesini","year":"2003","journal-title":"Hepatol Baltimore"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1038\/s41419-020-03003-w","article-title":"Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?","volume":"11","author":"Rada","year":"2020","journal-title":"Cell Death Dis"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"E281","DOI":"10.1152\/ajpendo.00332.2002","article-title":"Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites","volume":"284","author":"Lam","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1097\/HEP.0000000000000696","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Lazarus","year":"2023","journal-title":"J Hepatol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1111\/apt.17411","article-title":"Editorial: should NAFLD be included in the definition of metabolic syndrome?","volume":"57","author":"Colosimo","year":"2023","journal-title":"Aliment Pharmacol Ther"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1038\/nm.3372","article-title":"Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin","volume":"19","author":"Fullerton","year":"2013","journal-title":"Nat Med"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1111\/jgh.16272","article-title":"AMPK\/mTOR pathway significance in healthy liver and non-alcoholic fatty liver disease and its progression","volume":"38","author":"Marcondes-de-Castro","year":"2023","journal-title":"J Gastroenterol Hepatol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"eabq1984","DOI":"10.1126\/sciadv.abq1984","article-title":"Macrophage acetyl-CoA carboxylase regulates acute inflammation through control of glucose and lipid metabolism","volume":"8","author":"Yeudall","year":"2022","journal-title":"Science"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.2337\/db10-0393","article-title":"Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity","volume":"60","author":"Kim","year":"2011","journal-title":"Diabetes"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.cmet.2011.03.009","article-title":"AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice","volume":"13","author":"Li","year":"2011","journal-title":"Cell Metab"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s12944-018-0762-0","article-title":"Metformin attenuates triglyceride accumulation in HepG2 cells through decreasing stearyl-coenzyme a desaturase 1 expression","volume":"17","author":"Zhu","year":"2018","journal-title":"Lipids Health Dis"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"155516","DOI":"10.1016\/j.metabol.2023.155516","article-title":"Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis","volume":"141","author":"Park","year":"2023","journal-title":"Metab Clin Exp"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.plipres.2012.10.004","article-title":"Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease","volume":"52","author":"Leamy","year":"2013","journal-title":"Prog Lipid Res"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1080\/13813455.2018.1444058","article-title":"Grape seed proanthocyanidins and metformin combination attenuate hepatic endoplasmic reticulum stress in rats subjected to nutrition excess","volume":"125","author":"Yogalakshmi","year":"2019","journal-title":"Arch Physiol Biochem"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e97868","DOI":"10.1371\/journal.pone.0097868","article-title":"Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells","volume":"9","author":"Simon-Szab\u00f3","year":"2014","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"251","DOI":"10.3109\/08923970903252220","article-title":"Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells","volume":"32","author":"Kim","year":"2010","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"165621","DOI":"10.1016\/j.bbadis.2019.165621","article-title":"Protective effect of metformin against palmitate-induced hepatic cell death","volume":"1866","author":"Geng","year":"2020","journal-title":"Biochimica Et Biophysica Acta Mol Basis Dis"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.cmet.2011.11.004","article-title":"Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease","volume":"14","author":"Sunny","year":"2011","journal-title":"Cell Metab"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1194\/jlr.M023382","article-title":"Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver","volume":"53","author":"Satapati","year":"2012","journal-title":"J Lipid Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"66455","DOI":"10.18632\/oncotarget.12186","article-title":"CircRNA expression pattern and circRNA-miRNA-mRNA network in the pathogenesis of nonalcoholic steatohepatitis","volume":"7","author":"Jin","year":"2016","journal-title":"Oncotarget"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2986","DOI":"10.1038\/s41467-018-05383-2","article-title":"Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis","volume":"9","author":"Zhao","year":"2018","journal-title":"Nat Commun"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1016\/j.jhep.2018.08.008","article-title":"miRNAs in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis","volume":"69","author":"Liu","year":"2018","journal-title":"J Hepatol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"527","DOI":"10.18632\/aging.100184","article-title":"Controlling SIRT1 expression by microRNAs in health and metabolic disease","volume":"2","author":"Lee","year":"2010","journal-title":"Aging"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/nrgastro.2013.87","article-title":"MicroRNAs in liver disease","volume":"10","author":"Szabo","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"13729","DOI":"10.1038\/srep13729","article-title":"Effect of miR-34a in regulating steatosis by targeting PPAR\u03b1 expression in nonalcoholic fatty liver disease","volume":"5","author":"Ding","year":"2015","journal-title":"Sci Rep"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"101244","DOI":"10.1016\/j.molmet.2021.101244","article-title":"Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease","volume":"51","author":"Xu","year":"2021","journal-title":"Mol Metab"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"877","DOI":"10.3892\/ijmm.2015.2092","article-title":"MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis","volume":"35","author":"KATSURA","year":"2015","journal-title":"Int J Mol Med"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1038\/nm.4345","article-title":"Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug","volume":"23","author":"Wu","year":"2017","journal-title":"Nat Med"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1038\/aps.2016.21","article-title":"Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling","volume":"37","author":"Zhou","year":"2016","journal-title":"Acta Pharmacol Sin"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/labinvest.2012.75","article-title":"Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function","volume":"92","author":"Spruss","year":"2012","journal-title":"Lab Investig J Tech Meth Pathol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/j.jhep.2023.07.034","article-title":"FXR agonists in NASH treatment","volume":"79","author":"Adorini","year":"2023","journal-title":"J Hepatol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1038\/s41591-018-0222-4","article-title":"Gut microbiota and intestinal FXR mediate the clinical benefits of metformin","volume":"24","author":"Sun","year":"2018","journal-title":"Nat Med"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"54","DOI":"10.2337\/dc16-1324","article-title":"Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut","volume":"40","author":"de la Cuesta-Zuluaga","year":"2017","journal-title":"Diabetes Care"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"e1633235","DOI":"10.1080\/2162402X.2019.1633235","article-title":"Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy","volume":"8","author":"Verdura","year":"2019","journal-title":"Onco Targets Ther"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"763","DOI":"10.14218\/JCTH.2022.00415","article-title":"Akkermansia muciniphila and Bifidobacterium bifidum prevent NAFLD by regulating FXR expression and gut microbiota","volume":"11","author":"Nian","year":"2023","journal-title":"J Clin Transl Hepatol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1161\/CIRCULATIONAHA.115.019645","article-title":"Akkermansia Muciniphila protects against atherosclerosis by preventing metabolic Endotoxemia-induced inflammation in Apoe\u2212\/\u2212 mice","volume":"133","author":"Li","year":"2016","journal-title":"Circulation"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"9066","DOI":"10.1073\/pnas.1219451110","article-title":"Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity","volume":"110","author":"Everard","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref53","first-page":"262","article-title":"Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota","volume-title":"Nature","author":"Forslund","year":"2015"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"449","DOI":"10.4161\/gmic.21214","article-title":"Acetate-producing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters","volume":"3","author":"Fukuda","year":"2012","journal-title":"Gut Microbes"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1136\/gut.2008.165886","article-title":"Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability","volume":"58","author":"Cani","year":"2009","journal-title":"Gut"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1136\/jcp.31.5.395","article-title":"The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization","volume":"31","author":"Anthony","year":"1978","journal-title":"J Clin Pathol"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1053\/j.gastro.2013.04.005","article-title":"Underestimation of liver-related mortality in the United States","volume":"145","author":"Asrani","year":"2013","journal-title":"Gastroenterology"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"6668","DOI":"10.1038\/s41598-019-43228-0","article-title":"Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine","volume":"9","author":"Brandt","year":"2019","journal-title":"Sci Rep"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.bpg.2011.02.005","article-title":"Mechanisms of hepatic fibrogenesis","volume":"25","author":"Lee","year":"2011","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1002\/hep.25613","article-title":"Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis","volume":"56","author":"Lakner","year":"2012","journal-title":"Hepatol Baltimore"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1002\/hep.510230538","article-title":"Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis","volume":"23","author":"Baroni","year":"1996","journal-title":"Hepatol Baltimore"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.jhep.2018.11.034","article-title":"Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish","volume":"70","author":"de Oliveira","year":"2019","journal-title":"J Hepatol"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1002\/hep.21995","article-title":"Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells","volume":"47","author":"Caligiuri","year":"2008","journal-title":"Hepatol Baltimore"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"819","DOI":"10.3748\/wjg.v24.i7.819","article-title":"Metformin attenuates motility, contraction, and fibrogenic response of hepatic stellate cells and by activating AMP-activated protein kinase","volume":"24","author":"Li","year":"2018","journal-title":"World J Gastroenterol"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1002\/hep.21991","article-title":"High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase","volume":"47","author":"Adachi","year":"2008","journal-title":"Hepatol Baltimore"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.3390\/cells8111419","article-title":"TGF-\u03b2 in hepatic stellate cell activation and liver Fibrogenesis-updated 2019","volume":"8","author":"Dewidar","year":"2019","journal-title":"Cells"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1002\/jcp.22824","article-title":"AMP-activated protein kinase inhibits TGF-\u03b2-induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300","volume":"227","author":"Lim","year":"2012","journal-title":"J Cell Physiol"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.biopha.2017.03.079","article-title":"Metformin mitigates carbon tetrachloride-induced TGF-\u03b21\/Smad3 signaling and liver fibrosis in mice","volume":"90","author":"Fan","year":"2017","journal-title":"Biomed Pharmacother"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/1472-6882-12-156","article-title":"Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats","volume":"12","author":"Yao","year":"2012","journal-title":"BMC Complement Altern Med"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1111\/j.1478-3231.2009.02011.x","article-title":"Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice","volume":"29","author":"Latella","year":"2009","journal-title":"Liver Int"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"28597","DOI":"10.1038\/srep28597","article-title":"Metformin is a novel suppressor for transforming growth factor (TGF)-\u03b21","volume":"6","author":"Xiao","year":"2016","journal-title":"Sci Rep"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.bbrc.2015.06.023","article-title":"Succinate causes \u03b1-SMA production through GPR91 activation in hepatic stellate cells","volume":"463","author":"Li","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"e33411","DOI":"10.1371\/journal.pone.0033411","article-title":"Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis","volume":"7","author":"Noto","year":"2012","journal-title":"PLoS One"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1210\/jc.2012-1267","article-title":"Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis","volume":"97","author":"Zhang","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.bbrc.2015.03.148","article-title":"DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells","volume":"460","author":"Obara","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.cell.2009.03.046","article-title":"DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival","volume":"137","author":"Peterson","year":"2009","journal-title":"Cells"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1002\/cncr.21414","article-title":"Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies","volume":"104","author":"Ludwig","year":"2005","journal-title":"Cancer"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/j.1743-7563.2012.01535.x","article-title":"MG132, a proteasome inhibitor, induces apoptosis in tumor cells","volume":"9","author":"Guo","year":"2013","journal-title":"Asia Pac J Clin Oncol"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1172\/JCI89914","article-title":"Metabolic shifts in residual breast cancer drive tumor recurrence","volume":"127","author":"Havas","year":"2017","journal-title":"J Clin Invest"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of cancer metabolism","volume":"2","author":"DeBerardinis","year":"2016","journal-title":"Science"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.ccell.2019.03.007","article-title":"Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3\u03b2-MCL-1 Axis","volume":"35","author":"Elgendy","year":"2019","journal-title":"Cancer Cell"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/nrc3064","article-title":"Targeting hypoxia in cancer therapy","volume":"11","author":"Wilson","year":"2011","journal-title":"Nat Rev Cancer"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"2740","DOI":"10.1158\/1078-0432.CCR-09-2610","article-title":"Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis","volume":"16","author":"Liu","year":"2010","journal-title":"Clin Cancer Res"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"e81264","DOI":"10.1371\/journal.pone.0081264","article-title":"Effects of metformin on CD133+ colorectal cancer cells in diabetic patients","volume":"8","author":"Zhang","year":"2013","journal-title":"PLoS One"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.2353\/ajpath.2009.080596","article-title":"GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis","volume":"174","author":"Amann","year":"2009","journal-title":"Am J Pathol"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1158\/1078-0432.CCR-11-1877","article-title":"Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy","volume":"18","author":"McIntyre","year":"2012","journal-title":"Clin Cancer Res"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"873","DOI":"10.18632\/oncotarget.6418","article-title":"Metformin suppresses hypoxia-induced stabilization of HIF-1\u03b1 through reprogramming of oxygen metabolism in hepatocellular carcinoma","volume":"7","author":"Zhou","year":"2016","journal-title":"Oncotarget"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"116966","DOI":"10.1016\/j.lfs.2019.116966","article-title":"Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1\u03b1\/PFKFB3\/PFK1 pathway","volume":"239","author":"Hu","year":"2019","journal-title":"Life Sci Part 2"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"946","DOI":"10.2741\/4349","article-title":"Epigenetic regulation of hepatic tumor-initiating cells","volume":"20","author":"Ding","year":"2015","journal-title":"Front Biosci"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"3571","DOI":"10.12659\/MSM.907038","article-title":"Suppression of miR-21 expression inhibits cell proliferation and migration of liver Cancer cells by targeting phosphatase and Tensin homolog (PTEN)","volume":"24","author":"Liu","year":"2018","journal-title":"Med Sci Monit"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"322","DOI":"10.3892\/ijo.2014.2419","article-title":"Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo","volume":"45","author":"Miyoshi","year":"2014","journal-title":"Int J Oncol"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"F19","DOI":"10.1677\/ERC-09-0184","article-title":"The role of let-7 in cell differentiation and cancer","volume":"17","author":"Boyerinas","year":"2010","journal-title":"Endocr Relat Cancer"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.tiv.2015.04.019","article-title":"Metformin, but not sitagliptin, enhances WP 631-induced apoptotic HepG2 cell death","volume":"29","author":"Sliwinska","year":"2015","journal-title":"Toxicol Vitro"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"993","DOI":"10.7314\/APJCP.2016.17.3.993","article-title":"Effects of Epothilone a in combination with the antidiabetic drugs metformin and Sitagliptin in HepG2 human hepatocellular Cancer cells: role of transcriptional factors NF-\u03baB and p53","volume":"17","author":"Rogalska","year":"2016","journal-title":"Asian Pac J Cancer Prev"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s12072-017-9793-2","article-title":"CSH guidelines for the diagnosis and treatment of drug-induced liver injury","volume":"11","author":"Yu","year":"2017","journal-title":"Hepatol Int"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"s104","DOI":"10.7861\/clinmedicine.16-6-s104","article-title":"Drug-induced liver injury","volume":"16","author":"Katarey","year":"2016","journal-title":"Clin Med (Lond)"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1055\/s-0039-1679919","article-title":"Acetaminophen hepatotoxicity","volume":"39","author":"Ramachandran","year":"2019","journal-title":"Semin Liver Dis"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1053\/j.gastro.2012.06.004","article-title":"A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches","volume":"143","author":"Seki","year":"2012","journal-title":"Gastroenterology"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1093\/toxsci\/kfw158","article-title":"Editor's highlight: metformin protects against acetaminophen hepatotoxicity by attenuation of mitochondrial oxidant stress and dysfunction","volume":"154","author":"du","year":"2016","journal-title":"Toxicol Sci"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.bbrc.2015.08.009","article-title":"AMPK dependent protective effects of metformin on tumor necrosis factor-induced apoptotic liver injury","volume":"465","author":"Cai","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/j.intimp.2012.01.015","article-title":"Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice","volume":"12","author":"Yuan","year":"2012","journal-title":"Int Immunopharmacol"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1254\/jphs.93.501","article-title":"Metformin protects against carbon tetrachloride hepatotoxicity in mice","volume":"93","author":"Poon","year":"2003","journal-title":"J Pharmacol Sci"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1327814\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T14:57:39Z","timestamp":1702565859000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1327814\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,14]]},"references-count":102,"alternative-id":["10.3389\/fnut.2023.1327814"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2023.1327814","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,14]]},"article-number":"1327814"}}