{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:00:11Z","timestamp":1787029211734,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2024MC209"],"award-info":[{"award-number":["ZR2024MC209"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2019MH094"],"award-info":[{"award-number":["ZR2019MH094"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Xinjiang Tianchi Talent Project","award":["BT-2025-TCYC-0001"],"award-info":[{"award-number":["BT-2025-TCYC-0001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: The widespread adoption of high-fat diets has contributed to a rising incidence of metabolic disorders and associated cardiovascular diseases. This trend exacerbates myocardial ischemia\u2013reperfusion (I\/R) injury following interventional or thrombolytic therapy for acute myocardial infarction, leading to higher mortality and heart failure in affected individuals with metabolic dysregulation, for whom effective interventions are limited. Nuciferine, which possesses anti-inflammatory, antioxidant, and metabolic regulatory properties, has shown potential in improving post-I\/R cardiac function, yet its mechanism remains unclear. Methods: This study utilized an ex vivo mouse heart model perfused with high-glucose\/high-fatty acid solutions to establish a metabolic stress condition mimicking key aspects of the diabetic milieu and to evaluate the underlying mechanisms of nuciferine. Complementarily, a model of lipotoxicity combined with hypoxia\/reoxygenation (H\/R) injury was established in human cardiomyocyte cells (AC16). Results: Nuciferine significantly improved post-I\/R functional recovery and attenuated succinate accumulation, an effect comparable to the succinate dehydrogenase (SDH) inhibitor dimethyl malonate (DMM). Mechanistically, nuciferine bound to an SDH subunit, inhibiting its activity and subsequent reactive oxygen species (ROS) production via mitochondrial reverse electron transport (RET). It also activated Sirt1-dependent pathways, mitigating apoptosis and mitochondrial dysfunction in AC16 cardiomyocytes. The Sirtuin 1 (Sirt1) inhibitor selisistat (EX527) abolished nuciferine\u2019s protection, while DMM mirrored its efficacy, underscoring nuciferine\u2019s dual role in inhibiting SDH-mediated RET and activating Sirt1 in alleviating I\/R injury under metabolic stress conditions. Conclusions: These findings suggest that nuciferine confers cardioprotection by simultaneously attenuating RET-related oxidative stress and activating Sirt1.<\/jats:p>","DOI":"10.3390\/nu18030425","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T17:07:38Z","timestamp":1769533658000},"page":"425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nuciferine Ameliorates Lipotoxicity-Mediated Myocardial Ischemia\u2013Reperfusion Injury by Reducing Reverse Electron Transfer Mediated Oxidative Stress"],"prefix":"10.3390","volume":"18","author":[{"given":"Man","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Mitochondria and Healthy Aging, School of Life Sciences, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Shi","sequence":"additional","affiliation":[{"name":"Xinjiang Production and Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Mitochondria and Healthy Aging, School of Life Sciences, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Feng","sequence":"additional","affiliation":[{"name":"Center for Mitochondria and Healthy Aging, School of Life Sciences, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Diao","sequence":"additional","affiliation":[{"name":"Xinjiang Production and Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5743-0963","authenticated-orcid":false,"given":"Gang","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Mitochondria and Healthy Aging, School of Life Sciences, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Xinjiang Production and Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Science, Tarim University, Alar 843300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjun","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Mitochondria and Healthy Aging, School of Life Sciences, Yantai University, Yantai 264005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"357","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. 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