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Magnoflorine (MAG), a natural alkaloid from edible plants, ameliorates MASLD; however, its direct targets remain unclear. Here, by integrating thermal proteome profiling and disease target databases, we identified NADH ubiquinone oxidoreductase core subunit V1 (NDUFV1), a core subunit of mitochondrial Complex I, as a key target of MAG. MAG directly binds NDUFV1, suppresses mitochondrial electron transport chain activity, and alleviates lipid-induced reactive oxygen species (ROS) accumulation. In high-fat cell models and MASLD mice, MAG contributes to the restoration of AMP-activated protein kinase (AMPK) signaling, promoting fatty acid \u03b2-oxidation and inhibiting lipid biosynthesis to maintain lipid homeostasis. Notably, the lipid-lowering effects of MAG were significantly attenuated in NDUFV1-knockdown cells. This study reveals that MAG regulates lipid metabolism by targeting NDUFV1, highlighting its potential as a natural bioactive compound for MASLD.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c05636","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:01:43Z","timestamp":1791363703000},"page":"32318-32332","source":"Crossref","is-referenced-by-count":0,"title":["Magnoflorine Ameliorates\nMetabolic Dysfunction-Associated\nSteatotic Liver Disease by Targeting the NDUFV1 Subunit of Complex\nI to Regulate the ROS\/AMPK Signaling Pathway"],"prefix":"10.1021","volume":"74","author":[{"given":"Jiali","family":"Rao","sequence":"first","affiliation":[{"name":"Dalian University , , ,","place":["Dalian, China, 116622"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Li","sequence":"additional","affiliation":[{"name":"Dalian University , , ,","place":["Dalian, China, 116622"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushuang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dalian University , , ,","place":["Dalian, China, 116622"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1327-4428","authenticated-orcid":true,"given":"Juan","family":"Guo","sequence":"additional","affiliation":[{"name":"Dalian Institute of Marine Traditional Chinese Medicine , ,","place":["Dalian, China, 116622"]},{"name":"China Academy of Chinese Medical Sciences , , ,","place":["Beijing, China, 100000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baomin","family":"Feng","sequence":"additional","affiliation":[{"name":"Dalian University , , ,","place":["Dalian, China, 116622"]},{"name":"Dalian Institute of Marine Traditional Chinese Medicine , ,","place":["Dalian, China, 116622"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Lu","sequence":"additional","affiliation":[{"name":"Dalian University , , ,","place":["Dalian, China, 116622"]},{"name":"Dalian Institute of Marine Traditional Chinese Medicine , ,","place":["Dalian, China, 116622"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7778-0826","authenticated-orcid":true,"given":"Xiaoyao","family":"Ma","sequence":"additional","affiliation":[{"name":"Dalian University , , ,","place":["Dalian, China, 116622"]},{"name":"Dalian Institute of Marine Traditional Chinese Medicine , ,","place":["Dalian, China, 116622"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"issue":"5","key":"2026102109084688900_cit1","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/s41575-025-01045-z","article-title":"\u039cetabolic dysfunction-associated steatotic liver\ndisease: a condition of heterogeneous metabolic risk factors, mechanisms\nand comorbidities requiring holistic treatment","volume":"22","author":"Byrne","year":"2025","journal-title":"Nat. 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Mol.\nSci."},{"issue":"6","key":"2026102109084688900_cit5","doi-asserted-by":"publisher","first-page":"6178","DOI":"10.1021\/acs.jmedchem.4c02153","article-title":"2FA-platform\ngenerates dual fatty acid-conjugated GLP-1 receptor agonist TE-8105\nwith enhanced diabetes, obesity, and NASH efficacy compared to semaglutide","volume":"68","author":"Wong","year":"2025","journal-title":"J. Med. Chem."},{"key":"2026102109084688900_cit6","doi-asserted-by":"publisher","first-page":"116426","DOI":"10.1016\/j.foodres.2025.116426","article-title":"Ginsenoside Rk1 ameliorates non-alcoholic\nfatty liver disease by\ntargeting CD36 to modulate the ampk signaling pathway","volume":"211","author":"Wu","year":"2025","journal-title":"Food Res. 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Clin. Exp. 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Mol. Genet."},{"issue":"5","key":"2026102109084688900_cit27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178132","article-title":"RNF41 interacts\nwith the VPS52 subunit of the GARP and EARP complexes","volume":"12","author":"Masschaele","year":"2017","journal-title":"PLoS One"},{"key":"2026102109084688900_cit28","doi-asserted-by":"publisher","first-page":"146905","DOI":"10.1016\/j.brainres.2020.146905","article-title":"The Vps52\nsubunit of the GARP and\nEARP complexes is a novel Arf6-interacting protein that negatively\nregulates neurite outgrowth of hippocampal neurons","volume":"1745","author":"Ibuchi","year":"1745","journal-title":"Brain Res."},{"issue":"10","key":"2026102109084688900_cit29","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1007\/s00109-017-1572-y","article-title":"VPS52 induces apoptosis\nvia cathepsin D in gastric cancer","volume":"95","author":"Zhang","year":"2017","journal-title":"J. Mol. Med."},{"issue":"22","key":"2026102109084688900_cit30","doi-asserted-by":"publisher","first-page":"6350","DOI":"10.1093\/hmg\/ddv344","article-title":"Characterization of\nclinically identified mutations in NDUFV1, the flavin-binding subunit\nof respiratory complex I, using a yeast model system","volume":"24","author":"Varghese","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2026102109084688900_cit31","doi-asserted-by":"publisher","first-page":"109690","DOI":"10.1016\/j.abb.2023.109690","article-title":"Effects of ROS pathway\ninhibitors and NADH and FADH2\nlinked substrates on mitochondrial bioenergetics and ROS emission\nin the heart and kidney cortex and outer medulla","volume":"744","author":"Sadri","year":"2023","journal-title":"Arch. Biochem. Biophys."},{"issue":"5","key":"2026102109084688900_cit32","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.3390\/cells9051229","article-title":"CTRP9 mediates\nprotective effects in cardiomyocytes via AMPK- and adiponectin receptor-mediated\ninduction of anti-oxidant response","volume":"9","author":"Niemann","year":"2020","journal-title":"Cells"},{"issue":"11","key":"2026102109084688900_cit33","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1007\/s12272-019-01178-1","article-title":"Molecular\ninsights into the role\nof mitochondria in non-alcoholic fatty liver disease","volume":"42","author":"Lee","year":"2019","journal-title":"Arch. Pharmacal Res."},{"issue":"3","key":"2026102109084688900_cit34","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1007\/s13679-022-00473-1","article-title":"Hepatocyte\nmitochondrial dynamics\nand bioenergetics in obesity-related non-alcoholic fatty liver disease","volume":"11","author":"Legaki","year":"2022","journal-title":"Curr. Obes. Rep."},{"issue":"1","key":"2026102109084688900_cit35","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1038\/s41467-017-01970-x","article-title":"The mitochondrial\nnegative regulator MCJ is a therapeutic target for acetaminophen-induced\nliver injury","volume":"8","author":"Barbier-Torres","year":"2017","journal-title":"Nat. Commun."},{"key":"2026102109084688900_cit36","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2020.02.025","article-title":"Role of oxidative\nstress in the pathogenesis of nonalcoholic fatty liver disease","volume":"152","author":"Chen","year":"2020","journal-title":"Free Radical Biol. Med."},{"issue":"3","key":"2026102109084688900_cit37","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1002\/cbin.11736","article-title":"Overexpression of NDUFV1\nalleviates renal damage by improving mitochondrial\nfunction in unilateral ureteral obstruction model mice","volume":"46","author":"Wang","year":"2022","journal-title":"Cell Biol. Int."},{"key":"2026102109084688900_cit38","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1146\/annurev-pathol-020117-043617","article-title":"Recent Insights\ninto the Pathogenesis\nof Nonalcoholic Fatty Liver Disease","volume":"13","author":"Arab","year":"2018","journal-title":"Annu. Rev.\nPathol."},{"issue":"4","key":"2026102109084688900_cit39","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1002\/hep.26226","article-title":"Mitochondrial\nadaptations and dysfunctions in nonalcoholic fatty liver disease","volume":"58","author":"Begriche","year":"2013","journal-title":"Hepatology"},{"issue":"3","key":"2026102109084688900_cit40","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial reactive oxygen species\n(ROS) and ROS-induced ROS release","volume":"94","author":"Zorov","year":"2014","journal-title":"Physiol.\nRev."},{"issue":"9","key":"2026102109084688900_cit41","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.3390\/ijms22094642","article-title":"The chemistry\nof reactive oxygen species (ROS) revisited: outlining their role in\nbiological macromolecules (DNA, lipids and proteins) and induced pathologies","volume":"22","author":"Juan","year":"2021","journal-title":"Int. J. Mol. Sci."},{"issue":"6","key":"2026102109084688900_cit42","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1007\/s00394-023-03179-9","article-title":"Aerobic exercise\nand vitamin E improve high-fat diet-induced NAFLD in rats by regulating\nthe AMPK pathway and oxidative stress","volume":"62","author":"Bai","year":"2023","journal-title":"Eur.\nJ. Nutr."},{"key":"2026102109084688900_cit43","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.biocel.2017.12.019","article-title":"Mitochondria\nin non-alcoholic fatty liver disease","volume":"95","author":"Simoes","year":"2018","journal-title":"Int. J.\nBiochem. Cell Biol."},{"issue":"7","key":"2026102109084688900_cit44","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1016\/j.bbabio.2015.12.009","article-title":"Energy conversion,\nredox catalysis and generation of\nreactive oxygen species by respiratory complex I","volume":"1857","author":"Hirst","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"issue":"6","key":"2026102109084688900_cit45","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/nrm3997","article-title":"A giant\nmolecular proton pump: structure and mechanism of respiratory complex\nI","volume":"16","author":"Sazanov","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"4","key":"2026102109084688900_cit46","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1080\/10715760290021270","article-title":"Coenzyme\nQ cytoprotective mechanisms for mitochondrial\ncomplex I cytopathies involves NAD(P)H: quinone oxidoreductase 1 (NQO1)","volume":"36","author":"Chan","year":"2002","journal-title":"Free Radical Res."},{"issue":"12","key":"2026102109084688900_cit47","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1161\/CIRCRESAHA.118.314284","article-title":"Ndufs2, a core subunit\nof mitochondrial complex I, is essential for acute oxygen-sensing\nand hypoxic pulmonary vasoconstriction","volume":"124","author":"Dunham-Snary","year":"2019","journal-title":"Circ.\nRes."},{"issue":"2","key":"2026102109084688900_cit48","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.apsb.2021.11.003","article-title":"Mitochondrial complex\nI as a therapeutic\ntarget for Alzheimer\u2019s disease","volume":"12","author":"Trushina","year":"2022","journal-title":"Acta\nPharm. 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