{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:30Z","timestamp":1787028570349,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["R01HL076179"],"award-info":[{"award-number":["R01HL076179"]}]},{"name":"National Institutes of Health (NIH)","award":["R35GM118337"],"award-info":[{"award-number":["R35GM118337"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hemorrhagic shock (HS) is a type of hypovolemic shock and is a leading cause of mortality worldwide. Enolase 1 (ENO1), a key enzyme in glycolysis, has been implicated in the pathogenesis of inflammatory disorders. We hypothesize that Kupffer cell (KC) ENO1 contributes to liver inflammation and that inhibiting ENO1 with ENOblock protects the liver from HS-induced injury. HS was induced in mice by lowering mean arterial pressure to 25 mmHg for 90 min, followed by fluid resuscitation. Twenty-four hours later, KCs were isolated. To mimic HS in vitro, KCs were isolated from healthy mice and exposed to hypoxia\/reoxygenation (H\/R). Hypoxic KCs were treated with ENOblock during reoxygenation, and cytokines (IL-1\u03b2, TNF-\u03b1, IL-6) were measured. In mice subjected to HS and treated with ENOblock, the liver was harvested. In KCs isolated from HS mice as well as in H\/R exposed KCs, ENO1 mRNA and protein expression were significantly increased. In KCs exposed to H\/R as well as in liver tissues from HS mice, cytokine mRNA and protein levels (IL-1\u03b2, TNF-\u03b1, IL-6) were increased; however, ENOblock treatment significantly decreased these parameters. HS also markedly increased ENO1 activity and cleaved caspase-1 in KCs, while these parameters were significantly attenuated by ENOblock treatment. These findings suggest that targeting ENO1 in KCs could be a promising therapeutic strategy for mitigating HS-induced liver injury.<\/jats:p>","DOI":"10.3390\/ijms26178340","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T10:29:18Z","timestamp":1756376958000},"page":"8340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting Kupffer Cell Enolase 1 Attenuates Liver Inflammation and Injury in Hemorrhagic Shock"],"prefix":"10.3390","volume":"26","author":[{"given":"Zhijian","family":"Hu","sequence":"first","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naureen","family":"Rashid","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8280-8999","authenticated-orcid":false,"given":"Asha","family":"Jacob","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-0394","authenticated-orcid":false,"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra\/Northwell, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13049-023-01088-8","article-title":"Traumatic hemorrhage and chain of survival","volume":"31","author":"Latif","year":"2023","journal-title":"Scand. J. Trauma Resusc. Emerg. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.7748\/ns.30.1.51.e9955","article-title":"Clinical features and management of haemorrhagic shock","volume":"30","author":"Gallimore","year":"2015","journal-title":"Nurs. Stand."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1097\/TA.0b013e3182a686ed","article-title":"Hemorrhagic shock","volume":"75","author":"Gann","year":"2013","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1002\/hep.30691","article-title":"Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock-Induced Liver Injury","volume":"70","author":"Xie","year":"2019","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"930419","DOI":"10.1155\/2014\/930419","article-title":"Myeloid knockout of HIF-1 \u03b1 does not markedly affect hemorrhage\/resuscitation-induced inflammation and hepatic injury","volume":"2014","author":"Wetzel","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.7150\/ijbs.63556","article-title":"Enolase 1, a Moonlighting Protein, as a Potential Target for Cancer Treatment","volume":"17","author":"Qiao","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/s41419-021-03823-4","article-title":"Colorectal cancer cell intrinsic fibroblast activation protein alpha binds to Enolase1 and activates NF-\u03baB pathway to promote metastasis","volume":"12","author":"Yuan","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cho, H., Lee, J.H., Um, J., Kim, S., Kim, Y., Kim, W.H., Kim, Y.S., Pagire, H.S., Ahn, J.H., and Ahn, Y. (2019). ENOblock inhibits the pathology of diet-induced obesity. Sci. Rep., 9.","DOI":"10.1038\/s41598-018-36715-3"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1007\/PL00000910","article-title":"Multifunctional alpha-enolase: Its role in diseases","volume":"58","author":"Pancholi","year":"2001","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"291","DOI":"10.4110\/in.2015.15.6.291","article-title":"The Anti-inflammatory Effect of GV1001 Mediated by the Downregulation of ENO1-induced Pro-inflammatory Cytokine Production","volume":"15","author":"Choi","year":"2015","journal-title":"Immune Netw."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1038\/s41388-020-1172-0","article-title":"Preclinical validation of Alpha-Enolase (ENO1) as a novel immunometabolic target in multiple myeloma","volume":"39","author":"Ray","year":"2020","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sedoris, K.C., Thomas, S.D., and Miller, D.M. (2010). Hypoxia induces differential translation of enolase\/MBP-1. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-157"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s12519-023-00698-7","article-title":"Biomarkers of hypoxic-ischemic encephalopathy: A systematic review","volume":"19","author":"Caramelo","year":"2023","journal-title":"World J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1161\/HYPERTENSIONAHA.122.19857","article-title":"Targeting Endothelial ENO1 (Alpha-Enolase) -PI3K-Akt-mTOR Axis Alleviates Hypoxic Pulmonary Hypertension","volume":"80","author":"Shi","year":"2023","journal-title":"Hypertension"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2318904121","DOI":"10.1073\/pnas.2318904121","article-title":"Single-cell RNA sequencing unveils unique transcriptomic signatures of endothelial cells and role of ENO1 in response to disturbed flow","volume":"121","author":"Chen","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/JLB.3A0620-128R","article-title":"Enolase-specific cross antibodies induce neutrophilic inflammation in the intestine","volume":"109","author":"Lin","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1186\/s12931-023-02583-3","article-title":"Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis","volume":"24","author":"Huang","year":"2023","journal-title":"Respir. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Tan, C., Ma, H., Chen, J., Ma, G., Jha, A., Tan, S., Zhu, Y., Liu, M., Liu, K., and Xiao, X. (2025). Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis. Adv. Sci., e02297.","DOI":"10.1002\/advs.202502297"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1039\/C0MB00089B","article-title":"Novel use of fluorescent glucose analogues to identify a new class of triazine-based insulin mimetics possessing useful secondary effects","volume":"7","author":"Jung","year":"2011","journal-title":"Mol. Biosyst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1021\/cb300687k","article-title":"A unique small molecule inhibitor of enolase clarifies its role in fundamental biological processes","volume":"8","author":"Jung","year":"2013","journal-title":"ACS Chem. Biol. J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cho, H., Um, J., Lee, J.H., Kim, W.H., Kang, W.S., Kim, S.H., Ha, H.H., Kim, Y.C., Ahn, Y.K., and Jung, D.W. (2017). ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes. Sci. Rep., 7.","DOI":"10.1038\/srep44186"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Shimizu, J., Murao, A., Lee, Y., Aziz, M., and Wang, P. (2024). Extracellular CIRP promotes Kupffer cell inflammatory polarization in sepsis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1411930"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1074\/jbc.M114.603589","article-title":"The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages","volume":"290","author":"Tan","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.7150\/ijbs.83141","article-title":"Keratin 17 covalently binds to alpha-enolase and exacerbates proliferation of keratinocytes in psoriasis","volume":"19","author":"Luo","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/s41419-020-03087-4","article-title":"Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis","volume":"11","author":"Yang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/SHK.0000000000000213","article-title":"Minocycline and doxycycline, but not tetracycline, mitigate liver and kidney injury after hemorrhagic shock\/resuscitation","volume":"42","author":"Kholmukhamedov","year":"2014","journal-title":"Shock"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1002\/pmic.200700919","article-title":"Deja vu in proteomics. A hit parade of repeatedly identified differentially expressed proteins","volume":"8","author":"Petrak","year":"2008","journal-title":"Proteomics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1042\/BST20140201","article-title":"Chemical genetics and its application to moonlighting in glycolytic enzymes","volume":"42","author":"Jung","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.cmet.2019.06.005","article-title":"A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer\u2019s Disease","volume":"30","author":"Baik","year":"2019","journal-title":"Cell Metab."},{"key":"ref_30","first-page":"628","article-title":"Metabolic reprogramming of macrophages and its involvement in inflammatory diseases","volume":"20","author":"Guo","year":"2021","journal-title":"EXCLI J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/bph.13139","article-title":"Microglial M1\/M2 polarization and metabolic states","volume":"173","author":"Orihuela","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5260","DOI":"10.7150\/ijbs.73890","article-title":"Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease","volume":"18","author":"Fan","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11010-023-04717-z","article-title":"Hirudin ameliorates myocardial ischemia-reperfusion injury in a rat model of hemorrhagic shock and resuscitation: Roles of NLRP3-signaling pathway","volume":"479","author":"Bai","year":"2024","journal-title":"Mol. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e13663","DOI":"10.7554\/eLife.13663","article-title":"Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death","volume":"5","author":"Sanman","year":"2016","journal-title":"eLife"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13280","DOI":"10.1038\/ncomms13280","article-title":"PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation","volume":"7","author":"Xie","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e581","DOI":"10.1002\/iid3.581","article-title":"Interactions between NLRP3 inflammasome and glycolysis in macrophages: New insights into chronic inflammation pathogenesis","volume":"10","author":"Yu","year":"2022","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s12931-024-02926-8","article-title":"Glycolytic enzyme PGK1 promotes M1 macrophage polarization and induces pyroptosis of acute lung injury via regulation of NLRP3","volume":"25","author":"Zhu","year":"2024","journal-title":"Respir. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"112839","DOI":"10.1016\/j.intimp.2024.112839","article-title":"Bergapten attenuates hemorrhagic shock induced multi-organ injury by inhibiting NLRP3 inflammasome activation and pyroptosis","volume":"140","author":"Rao","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.7150\/thno.82607","article-title":"Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia\/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes","volume":"13","author":"Du","year":"2023","journal-title":"Theranostics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1038\/s41467-023-41800-x","article-title":"FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1\/Nrf2 signaling pathway in male mice","volume":"14","author":"Tong","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"873","DOI":"10.7150\/ijms.51268","article-title":"Remote Ischemic Preconditioning Attenuates Hepatic Ischemia\/Reperfusion Injury after Hemorrhagic Shock by Increasing Autophagy","volume":"18","author":"Zhou","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e100202","DOI":"10.1136\/egastro-2025-100202","article-title":"New insights into liver injury and regeneration from single-cell transcriptomics","volume":"3","author":"Wen","year":"2025","journal-title":"eGastroenterology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ryans, K., Omosun, Y., McKeithen, D.N., Simoneaux, T., Mills, C.C., Bowen, N., Eko, F.O., Black, C.M., Igietseme, J.U., and He, Q. (2017). The immunoregulatory role of alpha enolase in dendritic cell function during Chlamydia infection. BMC Immunol., 18.","DOI":"10.1186\/s12865-017-0212-1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e143715","DOI":"10.1172\/jci.insight.143715","article-title":"Extracellular CIRP activates STING to exacerbate hemorrhagic shock","volume":"6","author":"Chen","year":"2021","journal-title":"JCI Insight."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1097\/SHK.0000000000002309","article-title":"A novel oligonucleotide mRNA mimic attenuates hemorrhage-induced acute lung injury","volume":"61","author":"Hu","year":"2024","journal-title":"Shock"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.imlet.2013.12.002","article-title":"An efficient method to isolate and culture mouse Kupffer cells","volume":"158","author":"Li","year":"2014","journal-title":"Immunol. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/SHK.0000000000001894","article-title":"Inhibition of the Interaction of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival in Hepatic Ischemia\/Reperfusion","volume":"57","author":"Borjas","year":"2022","journal-title":"Shock"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8340\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:22Z","timestamp":1760034862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8340"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":47,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178340"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178340","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]}}}