{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T15:01:18Z","timestamp":1785164478018,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jilin Provincial Research Foundation for the Department of Science and Technology of Jilin Province","award":["YDZJ202401251ZYTS"],"award-info":[{"award-number":["YDZJ202401251ZYTS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background and Aims: The glucose metabolism pattern of the liver is closely related to liver diseases. In recent years, alcoholic hepatitis, viral hepatitis, fatty liver and other diseases have become important liver diseases that impact people\u2019s lives. IL-33 (interleukin-33), as a member of the IL-1 cytokine family, and \u201calarmin\u201d play a multi-dimensional regulatory role in various physiological and pathological processes of the liver. Methods: This study, by integrating transcriptomic data analysis and in vitro and in vivo experiments, expounds on new insights into the regulation of hepatocyte fate by IL-33 through metabolic reprogramming and reveals the potential, new role of IL-33 as a regulatory factor of metabolism. Conclusions: Our research further confirmed that IL-33, in addition to serving as an alarm hormone, is also a key checkpoint for liver metabolism, capable of promoting oxidative phosphorylation in hepatocytes and antagonizing acute liver injury induced by CCl4.<\/jats:p>","DOI":"10.3390\/cells15151346","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:08:14Z","timestamp":1785161294000},"page":"1346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Reprogramming of the Liver by IL-33: A Protective Response to Acute Injury"],"prefix":"10.3390","volume":"15","author":[{"given":"Ying","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weinan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengrui","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenda","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101397","DOI":"10.1016\/j.mam.2025.101397","article-title":"Liver aging: Underlying mechanisms and therapeutic strategies","volume":"105","author":"Zhong","year":"2025","journal-title":"Mol. Asp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00416","DOI":"10.1042\/BSR20160385","article-title":"Liver glucose metabolism in humans","volume":"36","year":"2016","journal-title":"Biosci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"107990","DOI":"10.1016\/j.phrs.2025.107990","article-title":"The role of glycolysis in MASLD development: Pathogenesis and therapeutic strategies","volume":"221","author":"Shang","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.cmet.2024.05.003","article-title":"Metabolic reprogramming in liver fibrosis","volume":"36","author":"Horn","year":"2024","journal-title":"Cell Metab."},{"key":"ref_5","first-page":"1602","article-title":"Metabolic reprogramming and its clinical implication for liver cancer","volume":"78","author":"Yang","year":"2023","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1186\/s12967-023-04367-1","article-title":"Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: New insights from pathogenic mechanisms to clinically targeted therapy","volume":"21","author":"Zheng","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103302","DOI":"10.1016\/j.redox.2024.103302","article-title":"FDX1 downregulation activates mitophagy and the PI3K\/AKT signaling pathway to promote hepatocellular carcinoma progression by inducing ROS production","volume":"75","author":"Sun","year":"2024","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.canlet.2019.11.029","article-title":"Mitochondrial metabolic reprogramming: An important player in liver cancer progression","volume":"470","author":"Jin","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/imr.12619","article-title":"Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family","volume":"281","author":"Cayrol","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1016\/j.immuni.2021.09.010","article-title":"IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation","volume":"54","author":"Faas","year":"2021","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1161\/CIRCRESAHA.110.218867","article-title":"Interleukin-33 induces protective effects in adipose tissue inflammation during obesity in mice","volume":"107","author":"Miller","year":"2010","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1084\/jem.20071868","article-title":"IL-33 reduces the development of atherosclerosis","volume":"205","author":"Miller","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e129429","DOI":"10.1172\/jci.insight.129429","article-title":"Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors","volume":"6","author":"Scott","year":"2021","journal-title":"JCI Insight"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Barbier, L., Ferhat, M., Salam\u00e9, E., Robin, A., Herbelin, A., Gombert, J.M., Silvain, C., and Barbarin, A. (2019). Interleukin-1 Family Cytokines: Keystones in Liver Inflammatory Diseases. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02014"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1111\/j.1478-3231.2012.02802.x","article-title":"IL-33 and HMGB1 alarmins: Sensors of cellular death and their involvement in liver pathology","volume":"32","author":"Arshad","year":"2012","journal-title":"Liver Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104716","DOI":"10.1016\/j.micpath.2020.104716","article-title":"IL-33 ameliorates liver injury and inflammation in Poly I:C and Concanavalin-A induced acute hepatitis","volume":"150","author":"Khan","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/cmi.2017.147","article-title":"IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell\/IL-13\/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis","volume":"16","author":"Liang","year":"2019","journal-title":"Cell Mol. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.4093\/dmj.2024.0532","article-title":"Interleukin 33 Promotes Liver Sinusoidal Endothelial Cell Dysfunction and Hepatic Fibrosis in Diabetic Mice","volume":"49","author":"Chen","year":"2025","journal-title":"Diabetes Metab. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1002\/eji.201041332","article-title":"NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis","volume":"41","author":"Arshad","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, C., Liu, C., Zhang, J., Lu, Y., Jiang, B., Xiong, H., and Li, C. (2023). Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1296687"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101808","DOI":"10.1016\/j.molmet.2023.101808","article-title":"Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult","volume":"77","author":"Yiew","year":"2023","journal-title":"Mol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e153944","DOI":"10.1172\/jci.insight.153944","article-title":"Dichloroacetate improves systemic energy balance and feeding behavior during sepsis","volume":"7","author":"Oh","year":"2022","journal-title":"JCI Insight"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1111\/imm.70053","article-title":"Inhibition of Pyruvate Dehydrogenase Kinase 2 Alleviates Concanavalin A-Induced Acute Liver Injury by Regulating Myeloid-Derived Suppressor Cells","volume":"177","author":"Li","year":"2026","journal-title":"Immunology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e0547","DOI":"10.1097\/HC9.0000000000000547","article-title":"The pyruvate dehydrogenase kinase inhibitor dichloroacetate mitigates alcohol-induced hepatic inflammation and metabolic disturbances in mice","volume":"8","author":"Wu","year":"2024","journal-title":"Hepatol. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121652","DOI":"10.1016\/j.jep.2026.121652","article-title":"Shaoyao Gancao Decoction alleviates ulcerative colitis-associated secondary liver injury by inhibiting the phosphorylation of pyruvate dehydrogenase in macrophages","volume":"366","author":"Tang","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.imlet.2010.04.005","article-title":"Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice","volume":"131","author":"Xiang","year":"2010","journal-title":"Immunol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8138","DOI":"10.1111\/jcmm.15472","article-title":"Transcriptomic landscape profiling of metformin-treated healthy mice: Implication for potential hypertension risk when prophylactically used","volume":"24","author":"Meng","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1038\/s41419-018-1136-2","article-title":"Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis","volume":"9","author":"Dai","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1002\/hep.30563","article-title":"Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt\/\u03b2-Catenin Signaling","volume":"69","author":"Zhao","year":"2019","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"154484","DOI":"10.1016\/j.phymed.2022.154484","article-title":"Koumine regulates macrophage M1\/M2 polarization via TSPO, alleviating sepsis-associated liver injury in mice","volume":"107","author":"Jin","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wang, C., Ma, C., Gong, L., Guo, Y., Fu, K., Zhang, Y., Zhou, H., and Li, Y. (2021). Macrophage Polarization and Its Role in Liver Disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.803037"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.immuni.2009.06.011","article-title":"IL-33 raises alarm","volume":"31","author":"Lamkanfi","year":"2009","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cayrol, C. (2021). IL-33, an Alarmin of the IL-1 Family Involved in Allergic and Non Allergic Inflammation: Focus on the Mechanisms of Regulation of Its Activity. Cells, 11.","DOI":"10.3390\/cells11010107"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12964-023-01114-3","article-title":"IL-33\/ST2 antagonizes STING signal transduction via autophagy in response to acetaminophen-mediated toxicological immunity","volume":"21","author":"Wang","year":"2023","journal-title":"Cell Commun. Signal"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhang, H.M., Chen, X.J., Li, S.P., Zhang, J.M., Sun, J., Zhou, L.X., Zhou, G.P., Cui, B., Sun, L.Y., and Zhu, Z.J. (2022). ILC2s expanded by exogenous IL-33 regulate CD45+CD11b+F4\/80high macrophage polarization to alleviate hepatic ischemia-reperfusion injury. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.869365"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101820","DOI":"10.1016\/j.xcrm.2024.101820","article-title":"Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis","volume":"5","author":"Sabatini","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3350\/cmh.2022.0095","article-title":"Development and prognosis of hepatocellular carcinoma in patients with diabetes","volume":"29","author":"Nakatsuka","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1007\/s00125-023-05947-y","article-title":"100 years of glucagon and 100 more","volume":"66","author":"Holst","year":"2023","journal-title":"Diabetologia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1097\/HEP.0000000000001597","article-title":"HBV induces liver fibrosis through the generation of reactive oxygen species in a pyruvate-dependent manner","volume":"84","author":"Duan","year":"2025","journal-title":"Hepatology"},{"key":"ref_40","first-page":"1046","article-title":"PDK4 Regulates Inflammatory Injury in Acute-on-chronic Liver Failure by Phosphorylating STAT1-mediated M1 Polarization of Macrophages","volume":"13","author":"Dong","year":"2025","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1182\/bloodadvances.2023010100","article-title":"Mitochondrial pyruvate dehydrogenase kinases contribute to platelet function and thrombosis in mice by regulating aerobic glycolysis","volume":"7","author":"Flora","year":"2023","journal-title":"Blood Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103293","DOI":"10.1016\/j.redox.2024.103293","article-title":"CREG1 attenuates doxorubicin-induced cardiotoxicity by inhibiting the ferroptosis of cardiomyocytes","volume":"75","author":"Liu","year":"2024","journal-title":"Redox Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1346\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:24:00Z","timestamp":1785162240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/15\/1346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":42,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cells15151346"],"URL":"https:\/\/doi.org\/10.3390\/cells15151346","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}