{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T21:22:51Z","timestamp":1781299371381,"version":"3.54.1"},"reference-count":112,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T00:00:00Z","timestamp":1661472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP21fk0210075"],"award-info":[{"award-number":["JP21fk0210075"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["DK113645"],"award-info":[{"award-number":["DK113645"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["DK081817"],"award-info":[{"award-number":["DK081817"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["JP21fk0210075"],"award-info":[{"award-number":["JP21fk0210075"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK113645"],"award-info":[{"award-number":["DK113645"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK081817"],"award-info":[{"award-number":["DK081817"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.<\/jats:p>","DOI":"10.3390\/ijms23179679","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T01:39:19Z","timestamp":1661737159000},"page":"9679","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Molecular Changes in Relation to Alcohol Consumption and Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2681-0776","authenticated-orcid":false,"given":"Reina","family":"Sasaki-Tanaka","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjit","family":"Ray","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, and Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-508X","authenticated-orcid":false,"given":"Mitsuhiko","family":"Moriyama","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4477-6292","authenticated-orcid":false,"given":"Ratna B.","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1654-5385","authenticated-orcid":false,"given":"Tatsuo","family":"Kanda","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kanda, T., Goto, T., Hirotsu, Y., Moriyama, M., and Omata, M. (2019). Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061358"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.3748\/wjg.v24.i25.2661","article-title":"Apoptosis and non-alcoholic fatty liver diseases","volume":"24","author":"Kanda","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kanda, T., Goto, T., Hirotsu, Y., Masuzaki, R., Moriyama, M., and Omata, M. (2020). Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041525"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1055\/s-0038-1676806","article-title":"Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets","volume":"39","author":"Yang","year":"2019","journal-title":"Semin. Liver Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"518674","DOI":"10.1155\/2010\/518674","article-title":"TLRs, Alcohol, HCV, and Tumorigenesis","volume":"2010","author":"Machida","year":"2010","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.jhep.2010.08.016","article-title":"Hepatitis C virus and alcohol: Same mitotic targets but different signaling pathways","volume":"54","author":"Alisi","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2036.2009.04002.x","article-title":"Review article: The diagnosis and management of alcoholic hepatitis","volume":"30","author":"Cohen","year":"2009","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1002\/hep.510250120","article-title":"Excess weight risk factor for alcoholic liver disease","volume":"25","author":"Naveau","year":"1997","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver Fibrosis, but No Other Histologic Features, Is Associated with Long-term Outcomes of Patients with Nonalcoholic Fatty Liver Disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"308","DOI":"10.5009\/gnl18175","article-title":"Effects of Moderate Alcohol Drinking in Patients with Nonalcoholic Fatty Liver Disease","volume":"13","author":"Kwon","year":"2019","journal-title":"Gut Liver"},{"key":"ref_11","first-page":"157","article-title":"Ethanol metabolism in the gastrointestinal tract and its possible consequences","volume":"2","author":"Seitz","year":"1994","journal-title":"Alcohol Alcohol. Suppl."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Dooley, J.S., Lok, A.S.F., Garcia-Tsao, G., and Pinzani, M. (2018). Alcohol and the Liver. Sherlock\u2019s Diseases of the Liver and Biliary System, Wiley Blackwell. [13th ed.].","DOI":"10.1002\/9781119237662"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1126\/science.162.3856.917","article-title":"Ethanol oxidation by hepatic microsomes: Adaptive increase after ethanol feeding","volume":"162","author":"Lieber","year":"1968","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.170.3953.78","article-title":"Reduced nicotinamide-adenine dinucleotide phosphate oxidase: Activity enhanced by ethanol consumption","volume":"170","author":"Lieber","year":"1970","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1111\/acer.12396","article-title":"Dietary nicotinic acid supplementation ameliorates chronic alcohol-induced fatty liver in rats","volume":"38","author":"Li","year":"2014","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_16","first-page":"236","article-title":"Induction of cytochrome P-4502E1 in the human liver by ethanol is caused by a corresponding increase in encoding messenger RNA","volume":"17","author":"Takahashi","year":"1993","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1002\/hep.1840220312","article-title":"Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventure","volume":"22","author":"Zimmerman","year":"1995","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2174\/1389200217666160125113806","article-title":"Oxidative and Non-Oxidative Metabolomics of Ethanol","volume":"17","year":"2016","journal-title":"Curr. Drug Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/hep.510230206","article-title":"High incidence of ADH2*1\/ALDH2*1 genes among Japanese alcohol dependents and patients with alcoholic liver disease","volume":"23","author":"Tanaka","year":"1996","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1124\/dmd.104.002402","article-title":"The cyp2e1-humanized transgenic mouse: Role of cyp2e1 in acetaminophen hepatotoxicity","volume":"33","author":"Cheung","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.jhep.2008.10.020","article-title":"The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model","volume":"50","author":"Butura","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"490","DOI":"10.2119\/molmed.2014.00048","article-title":"Binge alcohol consumption aggravates oxidative stress and promotes pathogenesis of NASH from obesity-induced simple steatosis","volume":"20","author":"Minato","year":"2014","journal-title":"Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.2174\/1381612824666180410091511","article-title":"Cytochrome P450s and Alcoholic Liver Disease","volume":"24","author":"Lu","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_24","first-page":"90","article-title":"Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis","volume":"9","author":"Wang","year":"2021","journal-title":"Clin. Transl. Hepatol."},{"key":"ref_25","first-page":"131","article-title":"Cytokine response and oxidative stress produced by ethanol, acetaldehyde and endotoxin treatment in HepG2 cells","volume":"3","author":"Hernandez","year":"2001","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1016\/j.lfs.2003.11.001","article-title":"MAP kinase signaling in diverse effects of ethanol","volume":"74","author":"Aroor","year":"2004","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1055\/s-2004-832939","article-title":"Cellular signaling mechanisms in alcohol-induced liver damage","volume":"24","author":"Hoek","year":"2004","journal-title":"Semin. Liver Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.jhep.2014.10.009","article-title":"Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy","volume":"62","author":"Guo","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.18632\/aging.202325","article-title":"ALDH2 protects naturally aged mouse retina via inhibiting oxidative stress-related apoptosis and enhancing unfolded protein response in endoplasmic reticulum","volume":"13","author":"Long","year":"2020","journal-title":"Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"G432","DOI":"10.1152\/ajpgi.00109.2020","article-title":"Acetaldehyde suppresses HBV-MHC class I complex presentation on hepatocytes via induction of ER stress and Golgi fragmentation","volume":"319","author":"Ganesan","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1111\/acer.14595","article-title":"Differential cytotoxicity, ER\/oxidative stress, dysregulated AMPKalpha signaling, and mitochondrial stress by ethanol and its metabolites in human pancreatic acinar cells","volume":"45","author":"Srinivasan","year":"2021","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41572-018-0014-7","article-title":"Alcoholic liver disease","volume":"4","author":"Seitz","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: Pathogenesis and new therapeutic targets","volume":"41","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29342","DOI":"10.1074\/jbc.M202411200","article-title":"Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP)","volume":"277","author":"You","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1002\/hep.20309","article-title":"Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury","volume":"40","author":"Ji","year":"2004","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1074\/jbc.M008791200","article-title":"The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver","volume":"276","author":"Galli","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1053\/j.gastro.2004.09.049","article-title":"The role of AMP-activated protein kinase in the action of ethanol in the liver","volume":"127","author":"You","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1748-1716.2009.01970.x","article-title":"AMP-activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives","volume":"196","author":"Viollet","year":"2009","journal-title":"Acta Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jcmgh.2019.10.005","article-title":"Tributyrin Inhibits Ethanol-Induced Epigenetic Repression of CPT-1A and Attenuates Hepatic Steatosis and Injury","volume":"9","author":"Donde","year":"2020","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s00204-015-1543-4","article-title":"Experimental models of liver fibrosis","volume":"90","author":"Yanguas","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/ajg.2014.262","article-title":"Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: A prospective cohort study","volume":"109","author":"Sandahl","year":"2014","journal-title":"Am. J. Gastroenterol."},{"key":"ref_42","first-page":"300","article-title":"Endotoxin and Kupffer cell activation in alcoholic liver disease","volume":"27","author":"Wheeler","year":"2003","journal-title":"Alcohol Res. Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"172S","DOI":"10.1097\/01.alc.0000189278.30237.e9","article-title":"Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure","volume":"29","author":"Fukui","year":"2005","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jhep.2018.10.008","article-title":"Hepatocellular carcinoma in the setting of alcohol-related liver disease","volume":"70","author":"Nahon","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2018). Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects. Biomedicines, 6.","DOI":"10.3390\/biomedicines6040106"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1093\/carcin\/23.11.1781","article-title":"The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma","volume":"23","author":"Hu","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1002\/hep.26419","article-title":"Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: A critical role for E-selectin","volume":"58","author":"Bertola","year":"2013","journal-title":"Hepatology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1002\/hep.1840060217","article-title":"Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis","volume":"6","author":"Rajkovic","year":"1986","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1136\/gutjnl-2016-311861","article-title":"MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47(phox)-oxidative stress pathway in neutrophils","volume":"66","author":"Li","year":"2017","journal-title":"Gut"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jhep.2018.10.023","article-title":"Inflammatory pathways in alcoholic steatohepatitis","volume":"70","author":"Gao","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.imlet.2021.05.007","article-title":"Complement System in Alcohol-Associated Liver Disease","volume":"236","author":"Carneiro","year":"2021","journal-title":"Immunol. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1053\/j.gastro.2010.04.041","article-title":"Complement and alcoholic liver disease: Role of C1q in the pathogenesis of ethanol-induced liver injury in mice","volume":"139","author":"Cohen","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.yexmp.2014.09.004","article-title":"Increased activity of the complement system in the liver of patients with alcoholic hepatitis","volume":"97","author":"Shen","year":"2014","journal-title":"Exp. Mol. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.imbio.2016.01.014","article-title":"Complement C5 controls liver lipid profile, promotes liver homeostasis and inflammation in C57BL\/6 genetic background","volume":"221","author":"Bavia","year":"2016","journal-title":"Immunobiology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1089\/ars.2010.3746","article-title":"Redox signaling and the innate immune system in alcoholic liver disease","volume":"15","author":"Cohen","year":"2011","journal-title":"Antioxid. Redox Signal"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bbrc.2005.04.088","article-title":"Ethanol alters cellular activation and CD14 partitioning in lipid rafts","volume":"332","author":"Dai","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.4049\/jimmunol.173.4.2715","article-title":"Suppression of innate immunity by acute ethanol administration: A global perspective and a new mechanism beginning with inhibition of signaling through TLR3","volume":"173","author":"Pruett","year":"2004","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"E4485","DOI":"10.1073\/pnas.1415174111","article-title":"Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity","volume":"111","author":"Leclercq","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1053\/j.gastro.2014.09.014","article-title":"Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice","volume":"148","author":"Chen","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1093\/alcalc\/agx025","article-title":"Gut-liver axis and sterile signals in the development of alcoholic liver disease","volume":"52","author":"Szabo","year":"2017","journal-title":"Alcohol Alcohol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1038\/nature07830","article-title":"The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex","volume":"458","author":"Park","year":"2009","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.imlet.2013.03.006","article-title":"Lipopolysaccharide blocks induction of unfolded protein response in human hepatoma cell lines","volume":"152","author":"Jiang","year":"2013","journal-title":"Immunol. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.1172\/JCI60777","article-title":"IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice","volume":"122","author":"Petrasek","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3727\/105221618X15325235888914","article-title":"Cellular Abnormalities and Emerging Biomarkers in Alcohol-Associated Liver Disease","volume":"19","author":"Singal","year":"2018","journal-title":"Gene Expr."},{"key":"ref_65","first-page":"499","article-title":"IgA in alcoholic cirrhosis","volume":"52","author":"Kalsi","year":"1983","journal-title":"Clin. Exp. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1365-2249.2009.04004.x","article-title":"Increased immunoglobulin A in alcoholic liver cirrhosis: Exploring the response of B cells to Toll-like receptor 9 activation","volume":"158","author":"Massonnet","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_67","first-page":"127","article-title":"Regulation of peripheral blood B-cell IgA production in alcoholic cirrhosis","volume":"30","author":"Allison","year":"1989","journal-title":"J. Clin. Lab. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"66S","DOI":"10.1111\/j.1530-0277.2002.tb02705.x","article-title":"Estriol enhances lipopolysaccharide-induced increases in nitric oxide production by Kupffer cells via mechanisms dependent on endotoxin","volume":"26","author":"Enomoto","year":"2002","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nature24302","article-title":"Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity","volume":"551","author":"Shalapour","year":"2017","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","article-title":"NASH limits anti-tumour surveillance in immunotherapy-treated HCC","volume":"592","author":"Pfister","year":"2021","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1053\/j.gastro.2014.06.043","article-title":"Roles for chemokines in liver disease","volume":"147","author":"Marra","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_72","first-page":"41","article-title":"Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration","volume":"18","author":"Sheron","year":"1993","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/(SICI)1096-9896(199809)186:1<82::AID-PATH151>3.0.CO;2-D","article-title":"Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis","volume":"186","author":"Afford","year":"1998","journal-title":"J. Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"155402","DOI":"10.1016\/j.cyto.2020.155402","article-title":"IL-8 exacerbates alcohol-induced fatty liver disease via the Akt\/HIF-1\u03b1 pathway in human IL-8-expressing mice","volume":"138","author":"Wang","year":"2021","journal-title":"Cytokine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1136\/gutjnl-2013-306098","article-title":"CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis","volume":"63","author":"Altamirano","year":"2014","journal-title":"Gut"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"173090","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1111\/j.1365-2249.2012.04609.x","article-title":"Hepatic expression of CCL2 in alcoholic liver disease is associated with disease severity and neutrophil infiltrates","volume":"169","author":"Lemmers","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1046\/j.1440-1746.2001.02528.x","article-title":"Comparison of truncal hair distribution in alcoholic liver disease and alcohol-related chronic pancreatitis","volume":"16","author":"Kumar","year":"2001","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"G342","DOI":"10.1152\/ajpgi.2001.281.2.G342","article-title":"Downregulation of nuclear sex steroid receptor activity correlates with severity of alcoholic liver injury","volume":"281","author":"Eagon","year":"2001","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"11066","DOI":"10.1128\/JVI.01300-08","article-title":"Hepatitis C virus core protein augments androgen receptor-mediated signaling","volume":"82","author":"Kanda","year":"2008","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1053\/j.gastro.2020.06.014","article-title":"Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1","volume":"159","author":"Innes","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Nunes Dos Santos, K., Florentino, R.M., Fran\u00e7a, A., Lima Filho, A.C.M., Santos, M.L.D., Missiaggia, D., Fonseca, M.C., Brasil Costa, I., Vidigal, P.V.T., and Nathanson, M.H. (2019). Polymorphism in the Promoter Region of NFE2L2 Gene Is a Genetic Marker of Susceptibility to Cirrhosis Associated with Alcohol Abuse. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143589"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1038\/ng.3417","article-title":"A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis","volume":"47","author":"Buch","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","author":"Romeo","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"144585","DOI":"10.1016\/j.gene.2020.144585","article-title":"PNPLA3 rs738409 is not associated with the risk of hepatocellular carcinoma and persistent infection of hepatitis B virus (HBV) in HBV-related subjects: A case-control study and meta-analysis on Asians","volume":"742","author":"Wang","year":"2020","journal-title":"Gene"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Nakamura, M., Kanda, T., Nakamoto, S., Miyamura, T., Jiang, X., Wu, S., and Yokosuka, O. (2013). No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081312"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Masuzaki, R., Kanda, T., Sasaki, R., Matsumoto, N., Ogawa, M., Matsuoka, S., Karp, S.J., and Moriyama, M. (2020). Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144906"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jhbp.245","article-title":"Recent advancement of molecular mechanisms of liver fibrosis","volume":"22","author":"Seki","year":"2015","journal-title":"J. Hepatobiliary Pancreat. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1136\/gut.2004.042127","article-title":"Human hepatic stellate cell lines, LX-1 and LX-2: New tools for analysis of hepatic fibrosis","volume":"54","author":"Xu","year":"2005","journal-title":"Gut"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/hep.29170","article-title":"Hepatitis C virus-induced CCL5 secretion from macrophages activates hepatic stellate cells","volume":"66","author":"Sasaki","year":"2017","journal-title":"Hepatology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e02225-16","DOI":"10.1128\/JVI.02225-16","article-title":"Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells","volume":"91","author":"Devhare","year":"2017","journal-title":"J. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1002\/hep.29346","article-title":"Hepatitis C virus-induced tumor-initiating cancer stem-like cells activate stromal fibroblasts in a xenograft tumor model","volume":"66","author":"Sasaki","year":"2017","journal-title":"Hepatology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/s41586-019-1897-5","article-title":"TGF-\u03b2 orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1","volume":"577","author":"Su","year":"2020","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1053\/jhep.2002.36155","article-title":"In vivo regulation of inducible no synthase in immune-mediated liver injury in mice","volume":"36","author":"Koerber","year":"2002","journal-title":"Hepatology"},{"key":"ref_95","first-page":"23","article-title":"The effects of interferon-alpha on the production and action of other cytokines","volume":"25","author":"Taylor","year":"1998","journal-title":"Semin. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Neubauer, K., Lindhorst, A., Tron, K., Ramadori, G., and Saile, B. (2008). Decrease of PECAM-1-gene-expression induced by proinflammatory cytokines IFN-gamma and IFN-alpha is reversed by TGF-beta in sinusoidal endothelial cells and hepatic mononuclear phagocytes. BMC Physiol., 8.","DOI":"10.1186\/1472-6793-8-9"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e23075","DOI":"10.1002\/jcla.23075","article-title":"Clinical characteristics analysis of 1180 patients with hepatocellular carcinoma secondary to hepatitis B, hepatitis C and alcoholic liver disease","volume":"34","author":"Zhao","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.ypmed.2003.11.027","article-title":"A meta-analysis of alcohol consumption and the risk of 15 diseases","volume":"38","author":"Corrao","year":"2004","journal-title":"Prev. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1093\/annonc\/mdu020","article-title":"Alcohol and liver cancer: A systematic review and meta-analysis of prospective studies","volume":"25","author":"Turati","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/s41416-018-0007-z","article-title":"Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project","volume":"118","author":"Petrick","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/hep.31288","article-title":"Epidemiology of Hepatocellular Carcinoma","volume":"73","author":"McGlynn","year":"2021","journal-title":"Hepatology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/hep.30623","article-title":"A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects from Hepatocellular Carcinoma Development in Alcoholic Liver Disease","volume":"70","author":"Yang","year":"2019","journal-title":"Hepatology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/ijc.31910","article-title":"PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases","volume":"144","author":"Yang","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"378A","DOI":"10.1111\/j.1530-0277.1996.tb01812.x","article-title":"Hepatocellular carcinoma associated with alcoholic liver disease: A clinicopathological study and genetic polymorphism of aldehyde dehydrogenase 2","volume":"20","author":"Ohhira","year":"1996","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/bjc.2014.579","article-title":"Alcohol consumption and site-specific cancer risk: A comprehensive dose-response meta-analysis","volume":"112","author":"Bagnardi","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/hed.25050","article-title":"Impact of alcohol dehydrogenase-aldehyde dehydrogenase polymorphism on clinical outcome in patients with hypopharyngeal cancer","volume":"40","author":"Shinomiya","year":"2018","journal-title":"Head Neck"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/carcin\/bgu244","article-title":"Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: The Japan Public Health Center-based prospective study","volume":"36","author":"Hidaka","year":"2015","journal-title":"Carcinogenesis"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1158\/1055-9965.EPI-09-0499","article-title":"Impact of multiple alcohol dehydrogenase gene polymorphisms on risk of upper aerodigestive tract cancers in a Japanese population","volume":"18","author":"Oze","year":"2009","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/cncr.22795","article-title":"Susceptibility to lung cancer and genetic polymorphisms in the alcohol metabolite-related enzymes alcohol dehydrogenase 3, aldehyde dehydrogenase 2, and cytochrome P450 2E1 in the Japanese population","volume":"110","author":"Minegishi","year":"2007","journal-title":"Cancer"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1159\/000362442","article-title":"Acute liver injury in a patient with alcohol dependence: A case resembling autoimmune hepatitis or drug-induced liver injury","volume":"8","author":"Hayashi","year":"2014","journal-title":"Case Rep. Gastroenterol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/B978-0-12-420118-7.00010-X","article-title":"Mixed \u03ba\/\u03bc partial opioid agonists as potential treatments for cocaine dependence","volume":"69","author":"Bidlack","year":"2014","journal-title":"Adv. Pharmacol."},{"key":"ref_112","first-page":"63","article-title":"Open-label Study with Nalmefene as Needed Use in Alcohol-Dependent Patients with Evidence of Elevated Liver Stiffness and\/or Hepatic Steatosis","volume":"55","author":"Mueller","year":"2020","journal-title":"Alcohol Alcohol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9679\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:15:49Z","timestamp":1760141749000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,26]]},"references-count":112,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms23179679"],"URL":"https:\/\/doi.org\/10.3390\/ijms23179679","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,26]]}}}