{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:14:47Z","timestamp":1778130887427,"version":"3.51.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myocardial ischemia-reperfusion injury (MIRI) remains a significant challenge in treating cardiovascular diseases, contributing to substantial myocardial damage and a poor prognosis. Traditional Chinese medicine (TCM) offers promising alternatives, with Xuan Bi Tong Yu Fang (XBTYF) being a classical formula known for its protective effects. However, the therapeutic mechanisms of XBTYF in MIRI have not been fully explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      MIRI was induced in 36 Wistar rats, which were randomly assigned to sham, model, XBTYF (high, medium, low dose), and positive control (Qishen Yiqi Droplet) groups (n = 6). Serum levels of CK, AST, and cTnI were measured, and myocardial injury was examined by TTC, HE, and Masson staining. Bulk RNA-seq was performed to analyze gene expression profiles. The chemical composition of XBTYF was characterized by UPLC-MS\/MS, followed by molecular docking to assess interactions between key compounds and Hoxb4.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , H9C2 cardiomyocytes were subjected to oxygen-glucose deprivation\/reoxygenation (OGD\/R) and treated with XBTYF. The role of Hoxb4 in regulating the Wnt\/\u03b2-catenin pathway was examined through gain- and loss-of-function approaches, together with the Wnt inhibitor IWR-1. Cell viability, proliferation, apoptosis, and the expression of apoptosis-related proteins and Wnt\/\u03b2-catenin pathway components were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      XBTYF treatment significantly reduced myocardial enzyme levels and myocardial infarction area in the MIRI rats. Histological analysis showed improved myocardial tissue structure and reduced fibrosis. Bulk RNA-seq analysis identified Hoxb4 as a key gene restored by XBTYF and revealed a significant suppressive effect of XBTYF on the Wnt\/\u03b2-catenin signaling pathway. Chemical analysis identified multiple bioactive compounds in XBTYF, and molecular docking further revealed that ginsenoside Rg3, a primary component, exhibited a strong binding affinity with the Hoxb4 protein.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies confirmed that XBTYF upregulated Hoxb4, promoting cell proliferation and inhibiting apoptosis under OGD\/R condition. Western blot analysis validated that XBTYF inhibited Wnt\/\u03b2-catenin signaling, which was associated with reduced apoptosis and improved myocardial protection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>XBTYF alleviates MIRI by upregulating Hoxb4 and subsequent inhibition of the Wnt\/\u03b2-catenin signaling pathway, leading to reduced cardiomyocyte apoptosis and providing cardio protection. Its effects may be linked to direct interactions between bioactive constituents, such as ginsenoside Rg3, and Hoxb4. Collectively, these findings provide mechanistic and experimental evidence supporting XBTYF as a potential adjunctive therapeutic strategy for ischemia-reperfusion-related myocardial injury and establish a molecular basis for its further translational investigation and clinical application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1767595","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:56:56Z","timestamp":1778129816000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hoxb4 upregulation by Xuan Bi Tong Yu Fang confers cardioprotection via repression of the Wnt\/\u03b2-catenin pathway in myocardial ischemia-reperfusion injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Peng-fei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Nephrology, Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han-ying","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian-ying","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the First Affiliated Hospital of Henan University of Chinese Medicine","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-yu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Third Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guang-yu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Research Center of Traditional Chinese Medicine, Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ai-dong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Third Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuang-di","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.48378","article-title":"Cardiovascular disorder risk assessment among police personnel in Bengaluru City, India, using World Health Organization\/International Society of Hypertension risk prediction chart","volume":"15","author":"S","year":"2023","journal-title":"Cureus"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000001209","article-title":"2024 heart disease and stroke statistics: a report of US and global data from the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab892","article-title":"European Society of Cardiology: cardiovascular disease statistics 2021","volume":"43","author":"Timmis","year":"2022","journal-title":"Eur Heart J"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2022.02.005","article-title":"Myocardial ischemia-reperfusion injury and the influence of inflammation","volume":"33","author":"Algoet","year":"2023","journal-title":"Trends Cardiovasc Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1172\/jci62874","article-title":"Myocardial ischemia-reperfusion injury: a neglected therapeutic target","volume":"123","author":"Hausenloy","year":"2013","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/s0415-6412(17)30083-8","article-title":"Traditional Chinese medicine for cardiovascular disease: evidence and potential mechanisms","volume":"69","author":"Hao","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2174\/1381612823666170925163427","article-title":"A review of Chinese herbal medicine for the treatment of chronic heart failure","volume":"23","author":"Wang","year":"2017","journal-title":"Curr Pharm Des"},{"key":"B8","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3892\/ijmm.2023.5312","article-title":"Tanshinone IIA confers protection against myocardial ischemia\/reperfusion injury by inhibiting ferroptosis and apoptosis via VDAC1","volume":"52","author":"Hu","year":"2023","journal-title":"Int J Mol Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2022.2117828","article-title":"Shenlian extract attenuates myocardial ischaemia-reperfusion injury via inhibiting M1 macrophage polarization by silencing miR-155","volume":"60","author":"Song","year":"2022","journal-title":"Pharm Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41401-018-0082-y","article-title":"Astragaloside IV attenuates myocardial ischemia\/reperfusion injury in rats via inhibition of calcium-sensing receptor-mediated apoptotic signaling pathways","volume":"40","author":"Yin","year":"2019","journal-title":"Acta Pharmacol Sin"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.109963","article-title":"MiR-30c-5p mediates the effects of panax notoginseng saponins in myocardial ischemia reperfusion injury by inhibiting oxidative stress-induced cell damage","volume":"125","author":"Wang","year":"2020","journal-title":"BioMed Pharmacother"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01057-y","article-title":"Notoginsenoside R1 protects against myocardial ischemia\/reperfusion injury in mice via suppressing TAK1-JNK\/p38 signaling","volume":"44","author":"Zeng","year":"2023","journal-title":"Acta Pharmacol Sin"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjtee.2022.06.008","article-title":"Pharmacological properties and mechanisms of Notoginsenoside R1 in ischemia-reperfusion injury","volume":"26","author":"Zhu","year":"2023","journal-title":"Chin J Traumatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.806216","article-title":"Inhibition of myocardial cell apoptosis is important mechanism for ginsenoside in the limitation of myocardial ischemia\/reperfusion injury","volume":"13","author":"Chen","year":"2022","journal-title":"Front Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1142\/s0192415x21500907","article-title":"Ginsenoside Rb1 inhibits cardiomyocyte autophagy via PI3K\/Akt\/mTOR signaling pathway and reduces myocardial ischemia\/reperfusion injury","volume":"49","author":"Qin","year":"2021","journal-title":"Am J Chin Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3390\/cimb47010044","article-title":"Notoginsenoside R1 attenuates H\/R injury in H9c2 cells by maintaining mitochondrial homeostasis","volume":"47","author":"Xu","year":"2025","journal-title":"Curr Issues Mol Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.709604","article-title":"Dehydrocorydaline protects against sepsis-induced myocardial injury through modulating the TRAF6\/NF-\u03baB pathway","volume":"12","author":"Li","year":"2021","journal-title":"Front Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/5041629","article-title":"Xuan Bi Tong Yu Fang promotes angiogenesis via VEGF-Notch1\/Dll4 pathway in myocardial ischemic rats","volume":"2020","author":"Li","year":"2020","journal-title":"Evid Based Complement Alternat Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2018.6957","article-title":"Protective effect of Qishen Yiqi dropping pills on the myocardium of rats with chronic heart failure","volume":"17","author":"Lu","year":"2019","journal-title":"Exp Ther Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"40684","DOI":"10.1038\/s41598-025-23707-3","article-title":"Smurf1 promotes gastric cancer progression by regulating Axin2-dependent Wnt signaling pathway","volume":"15","author":"Yu","year":"2025","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2018.340","article-title":"Low doses of nonylphenol promote growth of colon cancer cells through activation of ERK1\/2 via G protein\u2013coupled receptor 30","volume":"51","author":"Xie","year":"2019","journal-title":"Cancer Res Treat"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2023.104565","article-title":"Myocardial ischemia-reperfusion injury; molecular mechanisms and prevention","volume":"149","author":"Liu","year":"2023","journal-title":"Microvasc Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s40256-023-00614-4","article-title":"Cardioprotective strategies after ischemia-reperfusion injury","volume":"24","author":"Zhang","year":"2024","journal-title":"Am J Cardiovasc Drugs"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2174\/1389450117666160401120308","article-title":"Progress in therapies for myocardial ischemia reperfusion injury","volume":"18","author":"Chi","year":"2017","journal-title":"Curr Drug Targets"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1142\/s0192415x23500015","article-title":"Research progress of Chinese medicine in the treatment of myocardial ischemia-reperfusion injury","volume":"51","author":"Dong","year":"2023","journal-title":"Am J Chin Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/s41419-021-03411-6","article-title":"HOXB4 inhibits the proliferation and tumorigenesis of cervical cancer cells by downregulating the activity of Wnt\/\u03b2-catenin signaling pathway","volume":"12","author":"Lei","year":"2021","journal-title":"Cell Death Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.694238","article-title":"AKR1C3 and its transcription factor HOXB4 are promising diagnostic biomarkers for acute myocardial infarction","volume":"8","author":"Liang","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1155\/2024\/3373410","article-title":"The pharmacological mechanisms underlying the protective effect of ginsenoside Rg3 against heart failure","volume":"2024","author":"Jia","year":"2024","journal-title":"Cardiol Res Pract"},{"key":"B29","first-page":"104565","article-title":"Protopine regulates oxidative stress, apoptosis and autophagy in H9C2 cardiomyocytes under hypoxic conditions","volume":"149","author":"Ma","year":"2024"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-8703(96)90005-8","article-title":"Attenuation of the no-reflow phenomenon after coronary angioplasty for acute myocardial infarction with intracoronary papaverine","volume":"132","author":"Ishihara","year":"1996","journal-title":"Am Heart J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156532","article-title":"Ligustilide covalently binds to Cys254 of the creatine kinase, M-type protein, ameliorating acute myocardial ischemia by enhancing the creatine phosphate level","volume":"139","author":"Zhang","year":"2025","journal-title":"Phytomedicine"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1097\/mol.0000000000000445","article-title":"Wnt signaling in cardiovascular disease: opportunities and challenges","volume":"28","author":"Gay","year":"2017","journal-title":"Curr Opin Lipidol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41420-022-01212-0","article-title":"GPX4-independent ferroptosis-a new strategy in disease's therapy","volume":"8","author":"Ma","year":"2022","journal-title":"Cell Death Discov"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13912","article-title":"WNT\/\u03b2-catenin pathway is a key regulator of cardiac function and energetic metabolism","volume":"237","author":"Balatskyi","year":"2023","journal-title":"Acta Physiol (Oxf)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1157043","article-title":"The role of \u03b2-catenin in cardiac diseases","volume":"14","author":"Ni","year":"2023","journal-title":"Front Pharmacol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.2147\/jir.s319416","article-title":"Overexpression of HOXB4 promotes protection of bone marrow mesenchymal stem cells against lipopolysaccharide-induced acute lung injury partially through the activation of Wnt\/\u03b2-catenin signaling","volume":"14","author":"Lin","year":"2021","journal-title":"J Inflammation Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2023.10.010","article-title":"Regulated cell death in myocardial ischemia-reperfusion injury","volume":"35","author":"Xiang","year":"2024","journal-title":"Trends Endocrinol Metab"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1767595\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:56:57Z","timestamp":1778129817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1767595\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2026.1767595"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1767595","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"article-number":"1767595"}}