{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:05:12Z","timestamp":1792789512732,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"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":["82273309"],"award-info":[{"award-number":["82273309"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82273309"],"award-info":[{"award-number":["82273309"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Tongji Hospital Scientific Research Fund Project","award":["2023A14"],"award-info":[{"award-number":["2023A14"]}],"id":[{"id":"https:\/\/ror.org\/04xy45965","id-type":"ROR","asserted-by":"crossref"}]},{"award":["2023A14"],"award-info":[{"award-number":["2023A14"]}],"id":[{"id":"https:\/\/ror.org\/04xy45965","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Myocardial ischemia\u2013reperfusion injury (MIRI) remains a major complication in acute coronary syndrome and cardiac surgery, with oxidative stress and metabolic dysregulation serving as central pathogenic drivers. This study aimed to clarify whether the novel MyD88 inhibitor TJ-M2010-5 confers cardioprotection against MIRI by remodeling immune\u2013metabolic homeostasis, particularly through regulating NADPH oxidase (NOX)-derived reactive oxygen species (ROS) overproduction and endothelial nitric oxide synthase (eNOS) functional activity. In this study, male C57BL\/6 mice were subjected to 30 min myocardial ischemia followed by 24 h reperfusion, with or without TJ-M2010-5 pretreatment (50 mg\/kg, i.p.), and mouse cardiac vascular endothelial cells (H5V) were exposed to hypoxia\u2013reoxygenation (H\/R) with or without TJ-M2010-5 intervention. We systematically evaluated myocardial infarct size, ROS production, cell apoptosis, NF-\u03baB activation, NOX expression and activity, NADPH redox homeostasis, NO production, and eNOS phosphorylation levels. The results showed that TJ-M2010-5 significantly reduced myocardial infarct size and inhibited IKK\u03b2\/NF-\u03baB activation in I\/R-treated mice, and functionally disrupted MyD88 homodimerization in ischemic myocardium. In H\/R-challenged H5V cells, TJ-M2010-5 decreased ROS generation and cell apoptosis, suppressed NOX2\/NOX4 expression and activity, restored NADPH levels and NADP+\/NADPH redox balance, preserved tissue NO content, and maintained eNOS Ser1177 phosphorylation. In conclusion, pharmacologic blockade of MyD88 by TJ-M2010-5 alleviates NOX-dependent oxidative stress, stabilizes NADPH redox homeostasis, preserves NO bioavailability, and maintains eNOS functional activity, thereby exerting potent cardioprotective effects against MIRI via regulating redox homeostasis. The TLR\/MyD88\u2013NOX\/ROS\u2013eNOS signaling axis represents a novel and promising redox-regulatory therapeutic target for the clinical prevention and treatment of MIRI.<\/jats:p>","DOI":"10.3390\/ijms27188299","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blocking MyD88 Signaling Pathway Protects Against Myocardial Ischemia Reperfusion by Inhibiting NOX\/ROS Pathway and Enhancing eNOS Activity"],"prefix":"10.3390","volume":"27","author":[{"given":"Bo","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Xia","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Hubei Provincial Clinical Research Center for Organ Transplantation, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7058-0851","authenticated-orcid":false,"given":"Lin","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Hubei Provincial Clinical Research Center for Organ Transplantation, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1152\/physrev.00024.2007","article-title":"Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury","volume":"88","author":"Murphy","year":"2008","journal-title":"Physiol. 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