Objective To investigate the effect of exosomes derived from human adipose-derived mesenchymal stem cells preconditioned with Jiangzhi Yigan Decoction ( JZYGT-Exo) on ferroptosis in a metabolic dysfunction-associated fatty liver disease ( MAFLD ) cell model and the underlying mechanisms involved. Methods Human adipose-derived mesenchymal stem cells were treated with serum containing JZYGT to obtain JZYGT-Exo, which were characterized using transmission electron microscopy (TEM) and nanoparticle tracking. An in vitro MAFLD model was established by inducing human hepatoblastoma HepG2 cells with a mixture of oleic acid and palmitic acid. Model, JZYGT-Exo, JZYGT-Exo+Era group, and JZYGT-Exo+Fer-1 groups were created. Lipid metabolism was assessed by Oil Red O staining, and intracellular triglyceride ( TG) and glucose levels were measured. The cell viability was detected by the CCK-8 method. Levels of superoxide dismutase ( SOD ),malondialdehyde (MDA), reactive oxygen species (ROS), catalase (CAT), and glutathione peroxidase (GSH-Px) were detected. Mitochondrial membrane potential and morphology were evaluated using JC-1 and Mito-Tracker probes,respectively. Mitochondrial ultrastructure was observed by TEM, and glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 ( Nrf2 ) protein expression were detected by Western blot analysis. Results JZYGT-Exo were isolated and identified, and were effectively taken up by MAFLD model cells. JZYGT-Exo intervention significantly reduced intracellular lipid deposition as well as TG and glucose levels(P<0. 01,P<0. 001).Cell death mode screening indicated that JZYGT-Exo antagonized Erastin-induced ferroptosis. JZYGT-Exo increased SOD, CAT, and GSH-Px activities( P<0. 05), decreased MDA and ROS levels( P<0. 05,P<0. 01), enhanced mitochondrial membrane potential ( P<0. 05 ), improved mitochondrial morphology and ultrastructure, reduced mitochondrial iron deposition, and up-regulated GPX4 and Nrf2 protein expression( P<0. 01); these effects were partially reversed by Erastin and were enhanced by Fer-1. Conclusions JZYGT-Exo ameliorated lipid metabolism disorders and inhibited ferroptosis in MAFLD model cells by regulating key oxidative stress and ferroptosis proteins.Their mechanism of action may be related to Nrf2 / GPX4 signaling activation.