{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:22:23Z","timestamp":1790716943709,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2023-00219399"],"award-info":[{"award-number":["RS-2023-00219399"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR075037"],"award-info":[{"award-number":["RS-2022-NR075037"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>The signal transducer and activator of transcription 3 (STAT3) in myeloid cells suppresses proinflammatory cytokine production and reduces collagen deposition. However, its role in methionine- and choline-deficient (MCD) diet-fed mice remains unclear. This study investigates the effects of myeloid-specific STAT3 deficiency on hepatic inflammation and fibrosis in MCD diet-fed mice. Myeloid-specific STAT3 knockout (mSTAT3KO) mice were fed the MCD diet for four weeks to induce metabolic dysfunction-associated steatohepatitis (MASH). MCD diet-fed mice displayed MASH-like pathological phenotypes, including hepatic steatosis, inflammation, and fibrosis. Compared with MCD diet-fed WT mice, mSTAT3KO mice fed the MCD diet exhibited reduced hepatic lipid accumulation but increased fibrosis. Notably, mSTAT3KO mice showed elevated hepatic STAT3 and lipocalin-2 (LCN2) protein levels in hepatocytes. Some proinflammatory cytokines were increased by the MCD diet in mSTAT3KO mice, which also exhibited increased hepatocyte apoptosis. Conversely, MCD diet-induced CD36, perilipin-2, acyl-CoA thioesterase 2, and 4-hydroxynonenal proteins were reduced by mSTAT3KO. Myeloid-specific STAT3 deficiency may induce a compensatory STAT3\/LCN2 axis in hepatocytes, thereby exacerbating MASH progression.<\/jats:p>","DOI":"10.3390\/cells14191522","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T08:21:51Z","timestamp":1759220511000},"page":"1522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Myeloid-Specific STAT3 Deletion Aggravates Liver Fibrosis in Mice Fed a Methionine- and Choline-Deficient Diet via Upregulation of Hepatocyte-Derived Lipocalin-2"],"prefix":"10.3390","volume":"14","author":[{"given":"Kyung Eun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Joo","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong Seok","family":"An","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Ae","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yundong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwon","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwoo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewoong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Soon","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4010-9628","authenticated-orcid":false,"given":"Gu Seob","family":"Roh","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Metabolic Dysfunction Liver Disease Research Center, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Portincasa, P., Khalil, M., Mahdi, L., Perniola, V., Idone, V., Graziani, A., Baffy, G., and Di Ciaula, A. (2024). Metabolic Dysfunction-Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115640"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1002\/hep.30251","article-title":"Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis","volume":"69","author":"Younossi","year":"2019","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1194\/jlr.M800042-JLR200","article-title":"Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet","volume":"49","author":"Rinella","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \u201chits\u201d?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41423-020-00579-3","article-title":"Immunological mechanisms and therapeutic targets of fatty liver diseases","volume":"18","author":"Wang","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"536","DOI":"10.7150\/ijbs.7.536","article-title":"Signal transducer and activator of transcription 3 in liver diseases: A novel therapeutic target","volume":"7","author":"Wang","year":"2011","journal-title":"Int. J. Biol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1002\/hep.23532","article-title":"Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice","volume":"51","author":"Horiguchi","year":"2010","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1002\/hep.23430","article-title":"Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity","volume":"51","author":"Wang","year":"2010","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbadis.2013.01.014","article-title":"Protective effects of lipocalin-2 (LCN2) in acute liver injury suggest a novel function in liver homeostasis","volume":"1832","author":"Zimmermann","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Luo, L., Deng, L., Chen, Y., Ding, R., and Li, X. (2023). Identification of Lipocalin 2 as a Ferroptosis-Related Key Gene Associated with Hypoxic-Ischemic Brain Damage via STAT3\/NF-kappaB Signaling Pathway. Antioxidants, 12.","DOI":"10.3390\/antiox12010186"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/hep.32569","article-title":"Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob\/Ob mice","volume":"77","author":"Kim","year":"2023","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Shin, H.J., Kim, K.E., An, H.S., Jeong, E.A., Oh, J., Sun, Y., Park, D.J., Lee, J., Yang, J., and Roh, G.S. (2025). Carbon tetrachloride does not promote hepatic fibrosis in ob\/ob mice via downregulation of lipocalin-2 protein. Redox Biol., 80.","DOI":"10.1016\/j.redox.2025.103506"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1038\/npp.2017.93","article-title":"Dysfunction of Microglial STAT3 Alleviates Depressive Behavior via Neuron-Microglia Interactions","volume":"42","author":"Kwon","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-1-0716-2128-8_8","article-title":"Mouse Bone Marrow Cell Isolation and Macrophage Differentiation","volume":"2455","author":"Mendoza","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Charni-Natan, M., and Goldstein, I. (2020). Protocol for Primary Mouse Hepatocyte Isolation. STAR Protoc., 1.","DOI":"10.1016\/j.xpro.2020.100086"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_19","first-page":"2683","article-title":"Morphological and functional characterization of non-alcoholic fatty liver disease induced by a methionine-choline-deficient diet in C57BL\/6 mice","volume":"6","author":"Itagaki","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1016\/j.bbadis.2017.04.006","article-title":"Altered mitochondrial and peroxisomal integrity in lipocalin-2-deficient mice with hepatic steatosis","volume":"1863","author":"Asimakopoulou","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0163-7827(95)00011-9","article-title":"beta-oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: A century of continued progress","volume":"34","author":"Kunau","year":"1995","journal-title":"Prog. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1194\/jlr.M046961","article-title":"Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver","volume":"55","author":"Moffat","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1080\/15548627.2022.2128019","article-title":"Autophagic lysosome reformation in health and disease","volume":"19","author":"Nanayakkara","year":"2023","journal-title":"Autophagy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1053\/j.gastro.2015.09.015","article-title":"Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists","volume":"149","author":"Kleiner","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1002\/hep.30333","article-title":"Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis","volume":"69","author":"Farrell","year":"2019","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3727\/105221617X15093707969658","article-title":"Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights","volume":"18","author":"Stephenson","year":"2018","journal-title":"Gene Expr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1194\/jlr.M600198-JLR200","article-title":"Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1","volume":"47","author":"Rizki","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhao, J., Qi, Y.F., and Yu, Y.R. (2021). STAT3: A key regulator in liver fibrosis. Ann. Hepatol., 21.","DOI":"10.1016\/j.aohep.2020.06.010"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1053\/j.gastro.2008.01.016","article-title":"Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury","volume":"134","author":"Horiguchi","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"69","DOI":"10.4049\/jimmunol.2300151","article-title":"STAT3 Deficiency Alters the Macrophage Activation Pattern and Enhances Matrix Metalloproteinase 9 Expression during Staphylococcal Pneumonia","volume":"212","author":"Farmand","year":"2024","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Belloni, L., Di Cocco, S., Guerrieri, F., Nunn, A.D.G., Piconese, S., Salerno, D., Testoni, B., Pulito, C., Mori, F., and Pallocca, M. (2018). Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31835-2"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1074-7613(00)80005-9","article-title":"Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils","volume":"10","author":"Takeda","year":"1999","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.bbalip.2014.07.017","article-title":"Lipocalin-2 (LCN2) regulates PLIN5 expression and intracellular lipid droplet formation in the liver","volume":"1842","author":"Asimakopoulou","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.jhep.2016.05.041","article-title":"Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2","volume":"65","author":"Ye","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1267\/ahc.24-00046","article-title":"Effect of Hepatic Lipid Overload on Accelerated Hepatocyte Proliferation Promoted by HGF Expression via the SphK1\/S1PR2 Pathway in MCD-diet Mouse Partial Hepatectomy","volume":"57","author":"Choijookhuu","year":"2024","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Alshawsh, M.A., Alsalahi, A., Alshehade, S.A., Saghir, S.A.M., Ahmeda, A.F., Al Zarzour, R.H., and Mahmoud, A.M. (2022). A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet. Molecules, 27.","DOI":"10.3390\/molecules27030858"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1111\/jcmm.14108","article-title":"Pex11a deficiency causes dyslipidaemia and obesity in mice","volume":"23","author":"Chen","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"829","DOI":"10.4093\/dmj.2021.0274","article-title":"Peroxisomal Fitness: A Potential Protective Mechanism of Fenofibrate against High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice","volume":"46","author":"Jiang","year":"2022","journal-title":"Diabetes Metab. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1080\/21623945.2020.1776553","article-title":"The effect of Acot2 overexpression or downregulation on the preadipocyte differentiation in Chinese Red Steppe cattle","volume":"9","author":"Liu","year":"2020","journal-title":"Adipocyte"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12501","DOI":"10.1073\/pnas.0503132102","article-title":"Stearoyl-CoA desaturase-2 gene expression is required for lipid synthesis during early skin and liver development","volume":"102","author":"Miyazaki","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Pierce, A.A., Pickens, M.K., Siao, K., Grenert, J.P., and Maher, J.J. (2015). Differential hepatotoxicity of dietary and DNL-derived palmitate in the methionine-choline-deficient model of steatohepatitis. BMC Gastroenterol., 15.","DOI":"10.1186\/s12876-015-0298-y"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1146\/annurev-nutr-071813-105336","article-title":"Autophagy and Lipid Droplets in the Liver","volume":"35","author":"Singh","year":"2015","journal-title":"Annu. Rev. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100973","DOI":"10.1016\/j.mam.2021.100973","article-title":"Autophagy in liver diseases: A review","volume":"82","author":"Qian","year":"2021","journal-title":"Mol. Aspects Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Carotti, S., Aquilano, K., Zalfa, F., Ruggiero, S., Valentini, F., Zingariello, M., Francesconi, M., Perrone, G., Alletto, F., and Antonelli-Incalzi, R. (2020). Lipophagy Impairment Is Associated with Disease Progression in NAFLD. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00850"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"14321","DOI":"10.1016\/S0021-9258(18)67021-8","article-title":"Binding characteristics and affinity labeling of protein constituents of the human IM-9 lymphoblast receptor for substance P","volume":"261","author":"Payan","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Lin, Z., Yang, M., Yu, X., Tan, G., and Zhong, J. (2024). Ponatinib alleviates non-alcoholic steatohepatitis through TFEB-mediated autophagy. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1505768"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/19\/1522\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T08:35:44Z","timestamp":1759221344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/19\/1522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":47,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["cells14191522"],"URL":"https:\/\/doi.org\/10.3390\/cells14191522","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]}}}