Mazdutide Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Modulating Endoplasmic Reticulum Stress, Improving Lipid Metabolism and Alleviating Inflammation.
This study investigated whether mazdutide, a dual GLP-1/glucagon receptor agonist previously studied for weight and metabolic management, could reduce early-stage metabolic dysfunction-associated steatotic liver disease (MASLD). Researchers used two model systems: mice fed a high-fat diet for 12 weeks (then treated with subcutaneous mazdutide for 4 weeks) and hepatocytes exposed to free fatty acids in cell culture (then co-treated with mazdutide or an ER stress inhibitor). The study measured blood and liver lipid profiles, liver injury markers, inflammatory cytokines, oxidative stress indicators, and liver histology, as well as protein expression linked to endoplasmic reticulum (ER) stress, inflammation, and lipid metabolism. The authors report that mazdutide treatment was associated with improved lipid metabolism, reduced hepatic steatosis, lower liver injury markers, and decreased inflammation and oxidative stress in both the animal and cell models. Mechanistically, the authors propose that mazdutide acts at least partly by dampening ER stress pathways. Key limitations include the exclusive use of preclinical models (no human subjects), a single mouse strain/diet protocol, and the early-stage disease focus, meaning translation to human MASLD remains unestablished.