{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:38:24Z","timestamp":1790933904024,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"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":["82460848"],"award-info":[{"award-number":["82460848"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260845"],"award-info":[{"award-number":["82260845"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009110","name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","doi-asserted-by":"publisher","award":["2022D01D50"],"award-info":[{"award-number":["2022D01D50"]}],"id":[{"id":"10.13039\/100009110","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009110","name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","doi-asserted-by":"publisher","award":["2022D01A300"],"award-info":[{"award-number":["2022D01A300"]}],"id":[{"id":"10.13039\/100009110","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leading Talents in Scientific and Technological Innovation of Tianshan Mountain","award":["2023TSYCLJ0042"],"award-info":[{"award-number":["2023TSYCLJ0042"]}]},{"name":"Tianshan Talent Training Program: Youth Support Talent Program","award":["2023TSYCQQTJ0010"],"award-info":[{"award-number":["2023TSYCQQTJ0010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Necroptosis is a critical process in the pathogenesis of myocardial ischemia\u2013reperfusion injury (MIRI). Tilianin (Til), a natural flavonoid glycoside derived from Dracocephalum moldavica L., exhibits significant therapeutic potential in cardiovascular diseases. However, its efficacy and mechanisms in mitigating necroptosis-induced MIRI remain incompletely understood. This study aimed to elucidate the molecular mechanisms by which Til regulates cardiomyocyte necroptosis to alleviate MIRI. Methods: A rat model of MIRI was established by ligating the left anterior descending coronary artery. Necroptosis in H9c2 cardiomyocytes was induced by oxygen\u2013glucose deprivation\/reoxygenation (H\/R) combined with Z-VAD-FMK. Myocardial infarct size was assessed using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Histopathological injury in cardiac tissue was examined by hematoxylin\u2013eosin (HE) staining. Fluorescent probes were used to detect reactive oxygen species (ROS) and mitochondria. The molecular mechanics Poisson\u2013Boltzmann surface area (MM-PBSA) method was used to predict the binding energy between Til and RIP3. Furthermore, RIP3 overexpression and knockdown, along with inhibition of the downstream protein CaMKII, were used to further investigate the mechanism. Results: Til treatment significantly reduced MIRI in rats, decreased myocardial infarct size, histopathological injury, and regulated myocardial enzyme levels. Til pretreatment effectively inhibited necroptosis in H9c2 cells induced by H\/R and Z-VAD-FMK, as evidenced by reduced necroptosis rates, decreased inflammatory cytokine release, improved mitochondrial function, and suppressed phosphorylation of the necroptosis marker MLKL. Molecular docking and dynamics simulation demonstrated stable binding of Til to RIP3, which was verified through Western blot. The protective effects of Til on necroptosis were reversed by RIP3 overexpression. Furthermore, the CaMKII inhibitor KN93 abolished Til\u2019s effect on mitochondria. Conclusions: Til alleviates MIRI by targeting RIP3 to inhibit the necroptosis pathway and mPTP opening. These findings provide a new therapeutic strategy for MIRI and necroptosis-related diseases.<\/jats:p>","DOI":"10.3390\/ph19010084","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T17:24:58Z","timestamp":1767201898000},"page":"84","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tilianin Attenuates Myocardial Ischemia\u2013Reperfusion Injury by Targeting RIP3-Mediated Necroptosis"],"prefix":"10.3390","volume":"19","author":[{"given":"Ruifang","family":"Zheng","sequence":"first","affiliation":[{"name":"School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"},{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenling","family":"Su","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naihong","family":"Chen","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"},{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifeng","family":"Chu","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"},{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Xing","sequence":"additional","affiliation":[{"name":"Xinjiang Key Laboratory of Uygur Medical Research, Xinjiang Institute of Materia Medica, Urumqi 830004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1161\/CIRCRESAHA.123.322620","article-title":"Spatial Multiplexed Protein Profiling of Cardiac Ischemia-Reperfusion Injury","volume":"133","author":"Yao","year":"2023","journal-title":"Circ. 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