{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:03:15Z","timestamp":1783699395777,"version":"3.55.0"},"reference-count":34,"publisher":"Portland Press Ltd.","issue":"3","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U23A20398"],"award-info":[{"award-number":["U23A20398"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sichuan Science and Technology Program","award":["2025YFRG0005 2025ZNSFSC0662"],"award-info":[{"award-number":["2025YFRG0005 2025ZNSFSC0662"]}]},{"name":"Luzhou Science and Technology Project","award":["2023JYJ003"],"award-info":[{"award-number":["2023JYJ003"]}]},{"name":"Research Start-up Foundation of Southwest Medical University","award":["00040155"],"award-info":[{"award-number":["00040155"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2024ZD0537707"],"award-info":[{"award-number":["2024ZD0537707"]}]},{"name":"2025 Annual Commission-University Joint Innovation Fund Project of Chengdu Municipal Health Commission and Chengdu University of Traditional Chinese Medicine","award":["XYLH202501024"],"award-info":[{"award-number":["XYLH202501024"]}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,3,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sepsis-associated cardiac injury represents a significant complication of critical infections, leading to cardiac dysfunction, myocardial edema and myocardial inflammation. These manifestations result in severe target organ damage with an unfavorable prognosis and an elevated risk of mortality. The clearance of inflammatory immune cells infiltrating the heart and the attenuation of myocardial edema are key functions of the cardiac lymphatic system. The present study investigates the protective effects of 4-OI (4-octyl itaconate) against lipopolysaccharide (LPS)-mediated cardiac injury in a mouse model. We established acute cardiac dysfunction through intraperitoneal LPS injection and assessed cardiac function via small-animal ultrasound. Results indicated that LPS significantly impaired cardiac function, evidenced by decreased left ventricular ejection fraction (EF%) and fractional shortening (FS%). Treatment with 4-OI improved these parameters and reduced serum markers of myocardial injury, including cTnT and lactate dehydrogenase. Additionally, 4-OI mitigated LPS-induced cardiac edema and vascular leakage, as demonstrated by Evans Blue dye assays. Histological analyses revealed that 4-OI reduced inflammatory cell infiltration, particularly M1-type macrophages, and stabilized cardiac lymphatic endothelial function. To further elucidate the mechanism, we blocked lymphatic reflux via thoracic duct ligation, which diminished the therapeutic efficacy of 4-OI, indicating the involvement of cardiac lymphatics in its protective effects. Furthermore, in vitro studies showed that 4-OI reduced inflammatory responses in lymphatic endothelial cells and stabilized intercellular junctions disrupted by LPS. Network pharmacological analysis identified RhoA\/ROCK1 signaling as a potential target of 4-OI in treating LPS-induced endothelial dysfunction. In conclusion, 4-OI exhibits significant cardioprotective effects against LPS-induced acute cardiac dysfunction, primarily through modulation of inflammatory responses and stabilization of lymphatic endothelial function.<\/jats:p>","DOI":"10.1042\/cs20258569","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T08:40:51Z","timestamp":1771576851000},"page":"445-467","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["4-Octyl itaconate against septic cardiac injury by suppressing cardiac lymphatic vessel inflammation via the RhoA\u2013ROCK1 signaling pathway"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7646-0572","authenticated-orcid":false,"given":"Haoran","family":"Wu","sequence":"first","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglin","family":"Wang","sequence":"additional","affiliation":[{"name":"2School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ma","sequence":"additional","affiliation":[{"name":"3Department of Pharmacy, The Third People's Hospital of Yibin, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"4Department of Rehabilitation Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyun","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuting","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyi","family":"Tang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6559-3562","authenticated-orcid":false,"given":"Jinwei","family":"Pang","sequence":"additional","affiliation":[{"name":"5Southwest Medical University, Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7452-8973","authenticated-orcid":false,"given":"Rong","family":"Li","sequence":"additional","affiliation":[{"name":"6Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Luzhou Municipal Key Laboratory of Thrombosis and Vascular Biology, Laboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8303-6495","authenticated-orcid":false,"given":"Chunxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"2026030312264749900_B1","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1001\/jama.2024.3917","article-title":"Cardiac function before sepsis and clinical outcomes","volume":"331","author":"Iyer","year":"2024","journal-title":"JAMA"},{"key":"2026030312264749900_B2","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1056\/NEJMra2403213","article-title":"Sepsis and Septic Shock","volume":"391","author":"Meyer","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"2026030312264749900_B3","doi-asserted-by":"publisher","first-page":"i1585","DOI":"10.1136\/bmj.i1585","article-title":"Sepsis: pathophysiology and clinical management","volume":"353","author":"Gotts","year":"2016","journal-title":"BMJ"},{"key":"2026030312264749900_B4","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1038\/s41591-018-0213-5","article-title":"The Artificial Intelligence Clinician learns optimal treatment strategies for sepsis in intensive care","volume":"24","author":"Komorowski","year":"2018","journal-title":"Nat. Med."},{"key":"2026030312264749900_B5","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41569-018-0087-8","article-title":"Cardiac lymphatics in health and disease","volume":"16","author":"Brakenhielm","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"2026030312264749900_B6","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1161\/CIRCULATIONAHA.115.020143","article-title":"Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction","volume":"133","author":"Henri","year":"2016","journal-title":"Circulation"},{"key":"2026030312264749900_B7","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/s41392-024-02019-4","article-title":"EphrinB2-mediated CDK5\/ISL1 pathway enhances cardiac lymphangiogenesis and alleviates ischemic injury by resolving post-MI inflammation","volume":"9","author":"Bai","year":"2024","journal-title":"Signal Transduct. Target Ther."},{"key":"2026030312264749900_B8","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1093\/cvr\/cvac086","article-title":"Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure","volume":"119","author":"Heron","year":"2023","journal-title":"Cardiovasc. Res."},{"key":"2026030312264749900_B9","doi-asserted-by":"publisher","first-page":"113511","DOI":"10.1016\/j.intimp.2024.113511","article-title":"Lymphatic vessels are necessary for cardiac function and inflammation resolution in sepsis-induced cardiomyopathy","volume":"143","author":"Wu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"2026030312264749900_B10","doi-asserted-by":"publisher","first-page":"102938","DOI":"10.1016\/j.ebiom.2020.102938","article-title":"Therapeutic potential of tricarboxylic acid cycle metabolite itaconate in cardiovascular diseases","volume":"59","author":"Yang","year":"2020","journal-title":"eBioMedicine"},{"key":"2026030312264749900_B11","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/nature25986","article-title":"Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1","volume":"556","author":"Mills","year":"2018","journal-title":"Nature"},{"key":"2026030312264749900_B12","doi-asserted-by":"publisher","first-page":"e2400675121","DOI":"10.1073\/pnas.2400675121","article-title":"The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis","volume":"121","author":"Cyr","year":"2024","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026030312264749900_B13","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.bioactmat.2024.03.025","article-title":"Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing","volume":"37","author":"Zha","year":"2024","journal-title":"Bioact. Mater."},{"key":"2026030312264749900_B14","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s10020-023-00631-8","article-title":"4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling","volume":"29","author":"Xu","year":"2023","journal-title":"Mol. Med."},{"key":"2026030312264749900_B15","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1007\/s00011-023-01733-z","article-title":"4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition","volume":"72","author":"Wu","year":"2023","journal-title":"Inflamm. Res."},{"key":"2026030312264749900_B16","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s10020-025-01160-2","article-title":"4-Octyl itaconate alleviates endothelial cell inflammation and barrier dysfunction in LPS-induced sepsis via modulating TLR4\/MAPK\/NF-\u03baB signaling: 4-Octyl itaconate alleviates endothelial dysfunction","volume":"31","author":"Li","year":"2025","journal-title":"Mol. Med."},{"key":"2026030312264749900_B17","doi-asserted-by":"publisher","first-page":"1750.e1757","DOI":"10.1016\/j.cmet.2025.05.012","article-title":"Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury","volume":"37","author":"Shan","year":"2025","journal-title":"Cell Metab."},{"key":"2026030312264749900_B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI173034","article-title":"Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice","volume":"134","author":"Song","year":"2023","journal-title":"J. Clin. Invest."},{"key":"2026030312264749900_B19","doi-asserted-by":"publisher","first-page":"116535","DOI":"10.1016\/j.biopha.2024.116535","article-title":"Sacubitril\/Valsartan inhibits M1 type macrophages polarization in acute myocarditis by targeting C-type natriuretic peptide","volume":"174","author":"Liu","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"2026030312264749900_B20","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a041178","article-title":"Buttons and zippers: endothelial junctions in lymphatic vessels","volume":"12","author":"Baluk","year":"2022","journal-title":"Cold Spring Harb Perspect. Med."},{"key":"2026030312264749900_B21","doi-asserted-by":"publisher","first-page":"509","DOI":"10.3389\/fphys.2020.00509","article-title":"Lymphatic endothelial cell junctions: molecular regulation in physiology and diseases","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Physiol."},{"key":"2026030312264749900_B22","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12929-021-00730-w","article-title":"RhoA: a dubious molecule in cardiac pathophysiology","volume":"28","author":"Kilian","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"2026030312264749900_B23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.yexcr.2017.06.003","article-title":"Endothelial cell-cell adhesion and signaling","volume":"358","author":"Cerutti","year":"2017","journal-title":"Exp. Cell Res."},{"key":"2026030312264749900_B24","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.jare.2024.10.030","article-title":"Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy","volume":"75","author":"Wang","year":"2025","journal-title":"J. Adv. Res."},{"key":"2026030312264749900_B25","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.yjmcc.2024.08.003","article-title":"Mechanisms of the septic heart: from inflammatory response to myocardial edema","volume":"195","author":"Fan","year":"2024","journal-title":"J. Mol. Cell Cardiol."},{"key":"2026030312264749900_B26","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s40779-016-0099-9","article-title":"Pathophysiology of sepsis-induced myocardial dysfunction","volume":"3","author":"Lv","year":"2016","journal-title":"Mil. Med. Res."},{"key":"2026030312264749900_B27","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1152\/physrev.00052.2021","article-title":"The ebb and flow of cardiac lymphatics: a tidal wave of new discoveries","volume":"103","author":"Harris","year":"2023","journal-title":"Physiol. Rev."},{"key":"2026030312264749900_B28","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.jacc.2020.05.076","article-title":"Role of cardiac lymphatics in myocardial edema and fibrosis: JACC review topic of the week","volume":"76","author":"Brakenhielm","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"2026030312264749900_B29","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1016\/j.apsb.2021.09.017","article-title":"Ruscogenin alleviates LPS-triggered pulmonary endothelial barrier dysfunction through targeting NMMHC IIA to modulate TLR4 signaling","volume":"12","author":"Wu","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"2026030312264749900_B30","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1161\/CIRCRESAHA.123.322607","article-title":"Chylomicrons regulate lacteal permeability and intestinal lipid absorption","volume":"133","author":"Zarkada","year":"2023","journal-title":"Circ. Res."},{"key":"2026030312264749900_B31","doi-asserted-by":"publisher","first-page":"115077","DOI":"10.1016\/j.bcp.2022.115077","article-title":"S1PR2\/RhoA\/ROCK1 pathway promotes inflammatory bowel disease by inducing intestinal vascular endothelial barrier damage and M1 macrophage polarization","volume":"201","author":"Wang","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"2026030312264749900_B32","doi-asserted-by":"publisher","first-page":"109485","DOI":"10.1016\/j.cellsig.2019.109485","article-title":"Endothelial tight junctions and their regulatory signaling pathways in vascular homeostasis and disease","volume":"66","author":"Cong","year":"2020","journal-title":"Cell. Signal."},{"key":"2026030312264749900_B33","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1093\/cvr\/cvaa070","article-title":"The effects of sepsis on endothelium and clinical implications","volume":"117","author":"Dolmatova","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"2026030312264749900_B34","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.cyto.2008.01.006","article-title":"LPS\/TLR4 signal transduction pathway","volume":"42","author":"Lu","year":"2008","journal-title":"Cytokine"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/140\/3\/445\/984892\/cs-2025-8569.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/140\/3\/445\/984892\/cs-2025-8569.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:26:53Z","timestamp":1772558813000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/140\/3\/445\/237214\/4-Octyl-itaconate-against-septic-cardiac-injury-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":34,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3,11]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20258569","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2026,3]]}}}