{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:02:16Z","timestamp":1790744536865,"version":"4.1.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Though apelin is involved in cardiovascular, metabolic, and homeostasis disorders, its role in alcohol-associated liver disease (ALD) remains unclear. This study aimed to investigate the mechanism of apelin in promoting hepatic inflammation in ALD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RAW 264.7 macrophages and a chronic alcohol-fed C57BL\/6 mouse model were used. Apelin activated ERK1\/2 phosphorylation, and PD98059 pretreatment attenuated apelin-induced MCP-1 and PCNA expression. Inflammatory and proliferative markers (MCP-1, IL-6, PCNA) were assessed by qRT-PCR and western blot. ERK signaling was evaluated using the inhibitor PD98059. Liver pathology was examined by H&amp;amp;E and Oil Red O staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Alcohol upregulated apelin expression in RAW 264.7 cells. Apelin-13 increased MCP-1 and PCNA expression in time- and dose-dependent manners. Apelin overexpression enhanced, while siRNA knockdown reduced, inflammatory and proliferative gene expression. Apelin activated ERK1\/2 phosphorylation, and PD98059 pretreatment attenuated apelin-induced MCP-1 and PCNA expression.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , apelin overexpression exacerbated steatosis, ballooning degeneration, and inflammatory infiltration, with elevated MCP-1, IL-6, and PCNA levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Apelin aggravates inflammatory responses and hepatic steatosis in ALD via the ERK signaling pathway, suggesting that the apelin\/APJ\/p-ERK\/inflammation axis may represent a novel therapeutic target for ALD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1912482","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:45:55Z","timestamp":1790743555000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Apelin aggravates inflammatory response and hepatic steatosis in alcohol-associated liver disease via ERK signaling pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Hongyan","family":"Bian","sequence":"first","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]},{"name":"Oncology Department, The First Affiliated Hospital of Henan University","place":["Kaifeng, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aochun","family":"Wu","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlin","family":"Tang","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]},{"name":"Oncology Department, The First Affiliated Hospital of Henan University","place":["Kaifeng, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Song","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Meng","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xu","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Lv","sequence":"additional","affiliation":[{"name":"Kaifeng Key Laboratory for Infectious Diseases and Biosafety","place":["Kaifeng, China"]},{"name":"Oncology Department, The First Affiliated Hospital of Henan University","place":["Kaifeng, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7784","DOI":"10.3390\/ijms26167784","article-title":"Sex-dependent regulation of liver fibrosis in primary sclerosing cholangitis: the role of miR-125b, androgen receptors, TGF-\u03b2, and apelin signalling","volume":"26","author":"Abramczyk","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1683865","DOI":"10.3389\/fonc.2025.1683865","article-title":"The role of apelin in cancer","volume":"15","author":"Agarwala","year":"2025","journal-title":"Front. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e03","DOI":"10.15420\/cfr.2025.54","article-title":"Apelin\/APJ signalling as a potential complementary target for glucagon-like Peptide-1 receptor agonist therapy in heart failure","volume":"12","author":"Alfonso","year":"2026","journal-title":"Card. Fail Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s11427-015-4861-0","article-title":"Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K\/Akt and MEK\/Erk pathways","volume":"58","author":"Chen","year":"2015","journal-title":"Sci. China Life Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e0947","DOI":"10.1097\/hc9.0000000000000947","article-title":"The global epidemiology of alcohol-associated liver disease","volume":"10","author":"Danpanichkul","year":"2026","journal-title":"Hepatol. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"100130","DOI":"10.1016\/j.pharmr.2026.100130","article-title":"International union of basic and clinical pharmacology. CXXI. Apelin receptor pharmacology in the human cardiovascular system and emerging clinical applications","volume":"78","author":"Davenport","year":"2026","journal-title":"Pharmacol. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3735","DOI":"10.3390\/ijms24043735","article-title":"Alcohol, inflammation, and microbiota in alcohol-associated liver disease","volume":"24","author":"Duki\u0107","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e100104","DOI":"10.1136\/egastro-2024-100104","article-title":"Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease","volume":"2","author":"Gao","year":"2024","journal-title":"eGastroenterology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"101362","DOI":"10.1016\/j.jcmgh.2024.05.010","article-title":"A protein complex of liver origin activates a pro-inflammatory program that drives hepatic and intestinal injury in alcohol-associated liver disease","volume":"18","author":"Ge","year":"2024","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e178616","DOI":"10.1172\/JCI178616","article-title":"IL-8+ neutrophils drive inexorable inflammation in severe alcohol-associated hepatitis","volume":"134","author":"Guan","year":"2024","journal-title":"J. Clin. Invest"},{"key":"B11","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.neuroscience.2024.12.025","article-title":"Effects and mechanisms of apelin in treating central nervous system diseases","volume":"566","author":"Huang","year":"2025","journal-title":"Neuroscience"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2172","DOI":"10.3390\/genes13112172","article-title":"Distribution, function, and expression of the apelinergic system in the healthy and diseased mammalian brain","volume":"13","author":"Ivanov","year":"2022","journal-title":"Genes (Basel)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.7150\/ijms.101492","article-title":"Liver B cells promotes MASLD progression via the Apelin\/APLNR system","volume":"22","author":"Jiang","year":"2025","journal-title":"Int. J. Med. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"820002","DOI":"10.3389\/fendo.2022.820002","article-title":"The role of Apelin-APJ system in diabetes and obesity","volume":"13","author":"Li","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"109","DOI":"10.5009\/gnl14345","article-title":"Clinical implications of the serum apelin level on portal hypertension and prognosis of liver cirrhosis","volume":"10","author":"Lim","year":"2016","journal-title":"Gut Liver"},{"key":"B16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.cld.2025.08.004","article-title":"Alcohol-related liver disease: novel insights into mechanism","volume":"30","author":"Maddur","year":"2026","journal-title":"Clin. Liver Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1193150","DOI":"10.3389\/fendo.2023.1193150","article-title":"The role of apelinergic system in metabolism and reproductive system in normal and pathological conditions: an overview","volume":"14","author":"Mehri","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1136\/gut.2010.234690","article-title":"Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes","volume":"60","author":"Melgar-Lesmes","year":"2011","journal-title":"Gut"},{"key":"B19","doi-asserted-by":"publisher","first-page":"101223","DOI":"10.1016\/j.jhepr.2024.101223","article-title":"Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies","volume":"7","author":"Merens","year":"2025","journal-title":"JHEP Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"100854","DOI":"10.1016\/j.jhepr.2023.100854","article-title":"JNKs protect from cholestatic liver disease progression by modulating apelin signalling","volume":"5","author":"Mohamed","year":"2023","journal-title":"JHEP Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2986","DOI":"10.3390\/ijms26072986","article-title":"Apelin\/APJ: another player in the cancer biology network","volume":"26","author":"Naldi","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3390\/cells12010150","article-title":"The apelinergic system: apelin, ELABELA, and APJ action on cell apoptosis: anti-apoptotic or pro-apoptotic effect","volume":"12","author":"Respekta","year":"2022","journal-title":"Cells"},{"key":"B23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.ajpath.2025.05.023","article-title":"IL-6 trans-signaling regulates neutrophilic inflammation in alcohol-associated hepatitis","volume":"196","author":"Sarode","year":"2026","journal-title":"Am. J. Pathol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"104036","DOI":"10.1016\/j.mcn.2025.104036","article-title":"Stable apelin-13 analogues promote cell proliferation, differentiation and protect inflammation induced cell death","volume":"135","author":"Sharma","year":"2025","journal-title":"Mol. Cell Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1038\/s41423-025-01291-w","article-title":"Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease","volume":"22","author":"Shen","year":"2025","journal-title":"Cell Mol. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1292016","DOI":"10.3389\/fcell.2023.1292016","article-title":"Recent insight into the role of macrophage in alcohol-associated liver disease: a mini-review","volume":"11","author":"Sun","year":"2023","journal-title":"Front. Cell Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"90","DOI":"10.4291\/wjgp.v6.i4.90","article-title":"Alcoholic hepatitis: the pivotal role of kupffer cells","volume":"6","author":"Suraweera","year":"2015","journal-title":"World J. Gastrointest. Pathophysiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1016\/j.jhep.2020.07.016","article-title":"Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice","volume":"73","author":"Wang","year":"2020","journal-title":"J. Hepatol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"108822","DOI":"10.1016\/j.intimp.2022.108822","article-title":"Apelin\/APJ system in inflammation","volume":"109","author":"Wang","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1285788","DOI":"10.3389\/fendo.2023.1285788","article-title":"Beneficial effects of Apelin-13 on metabolic diseases and exercise","volume":"14","author":"Wen","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"10087","DOI":"10.3390\/ijms262010087","article-title":"The impact of the apelinergic system on the cardiovascular system","volume":"26","author":"Wyderka","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"4682","DOI":"10.3390\/ijms24054682","article-title":"Specificity proteins (SP) and kr\u00fcppel-like factors (KLF) in liver physiology and pathology","volume":"24","author":"Yerra","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3892\/mmr.2017.7919","article-title":"Apelin-13 promotes cell proliferation in the H9c2 cardiomyoblast cell line by triggering extracellular signal-regulated kinase 1\/2 and protein kinase B phosphorylation","volume":"17","author":"Yin","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e70152","DOI":"10.1111\/jcmm.70152","article-title":"Single-cell and spatial transcriptomics reveal apelin\/APJ pathway\u2019s role in microvessel formation and tumour progression in hepatocellular carcinoma","volume":"28","author":"Zhu","year":"2024","journal-title":"J. Cell Mol. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1912482\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:46:00Z","timestamp":1790743560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1912482\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":34,"alternative-id":["10.3389\/fphar.2026.1912482"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1912482","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"article-number":"1912482"}}