Mazdutide Ameliorates Non-Alcoholic Fatty Liver Disease by Modulating Endoplasmic Reticulum Stress
This preclinical study investigated whether mazdutide — a dual GLP-1/glucagon receptor agonist that has shown clinical promise for weight management and metabolic disorders — could alleviate non-alcoholic fatty liver disease (NAFLD) and explored its potential mechanism of action. Researchers induced NAFLD in mice via a 12-week high-fat diet, then treated animals with subcutaneous mazdutide for four weeks. Complementary in vitro experiments exposed hepatocytes to free fatty acids to model hepatic steatosis, followed by mazdutide co-treatment. The study measured serum and liver lipid profiles, liver injury markers, inflammatory cytokines, oxidative stress indicators, and key protein expression via Western blot and immunohistochemistry. Results indicated that mazdutide treatment was associated with reduced hepatic fat accumulation, lower liver injury markers, attenuated inflammation, and decreased oxidative stress in both models. Mechanistically, the authors attributed these effects to modulation of the PERK–eIF2α–ATF4–CHOP endoplasmic reticulum (ER) stress pathway, suppression of NF-κB-driven inflammation, and downregulation of lipogenic regulators (SREBP-1, C/EBPβ, PPARγ). Key limitations include the exclusive use of animal and cell-based models, lack of human data, and preprint status meaning findings have not yet undergone formal peer review.