Magnoflorine Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Targeting the NDUFV1 Subunit of Complex I to Regulate the ROS/AMPK Signaling Pathway

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited therapeutics. 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 β-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.