Mazdutide Ameliorates Non-Alcoholic Fatty Liver Disease by Modulating Endoplasmic Reticulum Stress

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder globally. Mazdutide has shown clinical benefits in weight management and metabolic regulation, indicating its potential as a therapeutic agent for NAFLD. This study aimed to investigate the efficacy and mechanism of action of Mazdutide against early-stage NAFLD. Methods: A NAFLD mouse model was induced by a 12-week high-fat diet, followed by a 4-week treatment with subcutaneous Mazdutide (100, 200, or 400 μg/kg). In vitro, a cellular NAFLD model was established by treating hepatocytes with 1 mM free fatty acids for 24 h, followed by co-treatment with Mazdutide (10, 20, or 50 nM) or the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid (4-PBA). Serum and hepatic lipid profiles, liver injury markers, and pro-inflammatory cytokines were quantified. Liver histopathology was assessed by hematoxylin and eosin and Oil Red O staining. Protein expression related to ER stress, inflammation, and lipid metabolism was analyzed by immunohistochemistry and Western blot. Results: Mazdutide treatment significantly ameliorated systemic and hepatic lipid metabolism disorders, reduced liver injury markers and hepatic steatosis, and mitigated inflammation and oxidative stress in NAFLD mice and hepatocytes. Mechanistically, Mazdutide alleviated ER stress by modulating the PERK-eIF2α-ATF4-CHOP pathway, suppressed the NF-κB-mediated inflammatory response, and downregulated key lipogenic regulators, including SREBP-1, C/EBPβ, and PPARγ. Conclusion: Our findings demonstrate that Mazdutide alleviates hepatic ER stress in NAFLD, leading to suppressed inflammatory responses and improved lipid metabolism, which ultimately attenuates disease progression.