{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:39:20Z","timestamp":1792521560111,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170606"],"award-info":[{"award-number":["82170606"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) 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 MASLD. This study aimed to investigate the efficacy and mechanism of action of Mazdutide against early-stage MASLD. Methods: A MASLD mouse model was induced by a 12-week high-fat diet, followed by a 4-week treatment with subcutaneous Mazdutide (100, 200, or 400 \u03bcg\/kg). In vitro, a cellular MASLD 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: Compared with the MASLD model group, Mazdutide treatment significantly ameliorated systemic and hepatic lipid metabolism disorders, reduced liver injury markers and hepatic steatosis, and mitigated inflammation and oxidative stress in MASLD mice and hepatocytes (p &lt; 0.05). Mechanistically, Mazdutide alleviated ER stress by modulating the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, suppressed the nuclear Factor kappa B (NF-\u03baB)-mediated inflammatory response, and downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT\/enhancer-binding protein beta (C\/EBP\u03b2), and peroxisome proliferator-activated receptor gamma (PPAR\u03b3) in both models (p &lt; 0.05). Conclusions: Our findings demonstrate that Mazdutide alleviates hepatic ER stress in MASLD, suppresses inflammatory responses and improved lipid metabolism, which ultimately attenuates disease progression.<\/jats:p>","DOI":"10.3390\/ph19030371","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:51:29Z","timestamp":1772117489000},"page":"371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mazdutide Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Modulating Endoplasmic Reticulum Stress, Improving Lipid Metabolism and Alleviating Inflammation"],"prefix":"10.3390","volume":"19","author":[{"given":"Liangyu","family":"Gan","sequence":"first","affiliation":[{"name":"College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8121-6940","authenticated-orcid":false,"given":"Lengxin","family":"Duan","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Huzhou College, Huzhou 313000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyi","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Drummer, C., Saaoud, F., Jhala, N.C., Cueto, R., Sun, Y., Xu, K., Shao, Y., Lu, Y., Shen, H., and Yang, L. (2023). Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1113883"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Turkseven, S., Turato, C., Villano, G., Ruvoletto, M., Guido, M., Bolognesi, M., Pontisso, P., and Di Pascoli, M. (2023). Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice. Antioxidants, 12.","DOI":"10.3390\/antiox12040971"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1097\/HEP.0000000000000520","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.4093\/dmj.2024.0541","article-title":"Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetes Mellitus: A Review and Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association","volume":"48","author":"Bae","year":"2024","journal-title":"Diabetes Metab. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s11427-023-2494-x","article-title":"RNA modifications in the progression of liver diseases: From fatty liver to cancer","volume":"67","author":"Li","year":"2024","journal-title":"Sci. China Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.jhep.2022.06.012","article-title":"Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease\u2014Novel insights into cellular communication circuits","volume":"77","author":"Peiseler","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"s86","DOI":"10.3350\/cmh.2022.0442","article-title":"Nonalcoholic fatty liver disease and non-liver comorbidities","volume":"29","author":"Manikat","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100096","DOI":"10.1016\/j.pharmr.2025.100096","article-title":"Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer","volume":"77","author":"Karin","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhou, L., Shen, H., Li, X., and Wang, H. (2022). Endoplasmic reticulum stress in innate immune cells\u2014A significant contribution to non-alcoholic fatty liver disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.951406"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"28390","DOI":"10.1021\/acs.jafc.4c07623","article-title":"Vitamin E Mitigates Apoptosis in Ovarian Granulosa Cells by Inhibiting Zearalenone-Induced Activation of the PERK\/eIF-2\u03b1\/ATF4\/Chop Signaling Pathway","volume":"72","author":"Liu","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1021\/acs.jafc.1c07733","article-title":"Preventive Effect of Apple Polyphenol Extract on High-Fat Diet-Induced Hepatic Steatosis in Mice through Alleviating Endoplasmic Reticulum Stress","volume":"70","author":"Yan","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13080","DOI":"10.1021\/acs.jafc.1c05213","article-title":"Erythritol Improves Nonalcoholic Fatty Liver Disease by Activating Nrf2 Antioxidant Capacity","volume":"69","author":"Jin","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"125997","DOI":"10.1016\/j.jhazmat.2021.125997","article-title":"Microglia-derived IL-1\u03b2 promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK\/eIF2\u03b1\/ATF4\/CHOP upon arsenic exposure","volume":"417","author":"Liu","year":"2021","journal-title":"J. Hazard. Mater."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/S2468-1253(22)00317-X","article-title":"Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: A systematic review and meta-analysis","volume":"8","author":"Quek","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1136\/gutjnl-2023-330110","article-title":"Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: An updated systematic review and meta-analysis","volume":"72","author":"Cho","year":"2023","journal-title":"Gut"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105791","DOI":"10.1016\/j.ebiom.2025.105791","article-title":"Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: Mechanistic insights from multi-omics analysis","volume":"117","author":"Dong","year":"2025","journal-title":"EBioMedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6869","DOI":"10.1111\/dom.70148","article-title":"Shared mechanistic pathways of glucagon signalling: Unlocking its potential for treating obesity, metabolic dysfunction-associated steatotic liver disease, and other cardio-kidney-metabolic conditions","volume":"27","author":"Neff","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8289","DOI":"10.1038\/s41467-023-44067-4","article-title":"A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity","volume":"14","author":"Ji","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"160","DOI":"10.2337\/dc23-1287","article-title":"Efficacy and Safety of Mazdutide in Chinese Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial","volume":"47","author":"Zhang","year":"2024","journal-title":"Diabetes Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e243780","DOI":"10.1148\/radiol.243780","article-title":"Multiparametric MRI Evaluation of Liver Fat and Iron after Glucagon-like Peptide-1 Receptor and Glucagon Receptor Dual-Agonist Treatment in a High-Fat Diet-induced Mouse Model","volume":"316","author":"Xia","year":"2025","journal-title":"Radiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1007\/s40265-025-02249-y","article-title":"Mazdutide: First Approval","volume":"85","author":"Shirley","year":"2025","journal-title":"Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nassir, F. (2022). NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules, 12.","DOI":"10.3390\/biom12060824"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hu, Z., Yue, H., Jiang, N., and Qiao, L. (2025). Diet, oxidative stress and MAFLD: A mini review. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1539578"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"149882","DOI":"10.1016\/j.bbrc.2024.149882","article-title":"Semaglutide alters gut microbiota and improves NAFLD in db\/db mice","volume":"710","author":"Mao","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Niu, S., Chen, S., Chen, X., Ren, Q., Yue, L., Pan, X., Zhao, H., Li, Z., and Chen, X. (2022). Semaglutide ameliorates metabolism and hepatic outcomes in an NAFLD mouse model. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1046130"},{"key":"ref_26","first-page":"26","article-title":"Semaglutide Ameliorates Hepatocyte Steatosis in a Cell Co-Culture System by Downregulating the IRE1\u03b1-XBP1-C\/EBP\u03b1 Signaling Pathway in Macrophages","volume":"110","author":"Hu","year":"2025","journal-title":"Pharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1038\/s41467-018-03941-2","article-title":"Targeting GLP-1 receptor trafficking to improve agonist efficacy","volume":"9","author":"Jones","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.1021\/acs.jproteome.5c00079","article-title":"Differential Role of Phosphorylation in Glucagon Family Receptor Signaling Revealed by Mass Spectrometry","volume":"24","author":"Lamb","year":"2025","journal-title":"J. Proteome Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1172\/JCI23621","article-title":"Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease","volume":"115","author":"Donnelly","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_30","first-page":"1","article-title":"Triglyceride Metabolism in the Liver","volume":"8","author":"Cohen","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106585","DOI":"10.1016\/j.phrs.2022.106585","article-title":"Secreted MUP1 that reduced under ER stress attenuates ER stress induced insulin resistance through suppressing protein synthesis in hepatocytes","volume":"187","author":"Gao","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s40364-024-00664-z","article-title":"Heat shock proteins (HSPs) in non-alcoholic fatty liver disease (NAFLD): From molecular mechanisms to therapeutic avenues","volume":"12","author":"Nie","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.canlet.2020.12.019","article-title":"ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc\/SREBP1 pathway","volume":"502","author":"Chen","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1007\/s00204-025-04052-w","article-title":"Lipogenesis and MASLD: Re-thinking the role of SREBPs","volume":"99","author":"Nakagawa","year":"2025","journal-title":"Arch. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s10565-025-10066-y","article-title":"The SDF-1\u03b1\/MTDH axis inhibits ferroptosis and promotes the formation of anti-VEGF-resistant choroidal neovascularization by facilitating the nuclear translocation of SREBP1","volume":"41","author":"Zou","year":"2025","journal-title":"Cell Biol. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4093\/dmj.2022.0367","article-title":"DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis","volume":"48","author":"Lee","year":"2024","journal-title":"Diabetes Metab. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/s41419-023-06317-7","article-title":"Deubiquitinase USP1 enhances CCAAT\/enhancer-binding protein beta (C\/EBP\u03b2) stability and accelerates adipogenesis and lipid accumulation","volume":"14","author":"Kim","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e0645","DOI":"10.1097\/HC9.0000000000000645","article-title":"C\/EBP\u03b2 transcription factor promotes alcohol-induced liver fibrosis in males via HDL remodeling","volume":"9","author":"Schonfeld","year":"2025","journal-title":"Hepatol. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1097\/HEP.0000000000000354","article-title":"Sepsis-induced endothelial dysfunction drives acute-on-chronic liver failure through Angiopoietin-2-HGF-C\/EBP\u03b2 pathway","volume":"78","author":"Elias","year":"2023","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114906","DOI":"10.1016\/j.ecoenv.2023.114906","article-title":"Short term exposure to polystyrene nanoplastics in mice evokes self-regulation of glycolipid metabolism","volume":"256","author":"He","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1016\/j.ijbiomac.2022.10.080","article-title":"Soybean soluble polysaccharide prevents obesity in high-fat diet-induced rats via lipid metabolism regulation","volume":"222","author":"He","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"137266","DOI":"10.1016\/j.ijbiomac.2024.137266","article-title":"Fucoidan alleviates hepatic lipid deposition by modulating the Perk-Eif2\u03b1-Atf4 axis via Sirt1 activation in Acanthopagrus schlegelii","volume":"282","author":"Zhao","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"117090","DOI":"10.1016\/j.envpol.2021.117090","article-title":"Organophosphorus pesticides exert estrogen receptor agonistic effect determined using Organization for Economic Cooperation and Development PBTG455, and induce estrogen receptor-dependent adipogenesis of 3T3-L1 adipocytes","volume":"283","author":"Kim","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1111\/jdv.19809","article-title":"Treponema pallidum protein Tp47 induced prostaglandin E2 to inhibit the phagocytosis in human macrophages","volume":"38","author":"Yi","year":"2024","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101349","DOI":"10.1016\/j.molmet.2021.101349","article-title":"The hepatocyte IKK: NF-\u03baB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis","volume":"54","author":"Heida","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"116707","DOI":"10.1016\/j.lfs.2019.116707","article-title":"The role of inflammation and endoplasmic reticulum stress in obesity-related cognitive impairment","volume":"233","author":"Liu","year":"2019","journal-title":"Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/path.6242","article-title":"Integrated transcriptomic landscape of the effect of anti-steatotic treatments in high-fat diet mouse models of non-alcoholic fatty liver disease","volume":"262","author":"Hidalgo","year":"2024","journal-title":"J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.7150\/ijbs.104778","article-title":"Metformin Alleviates Liver Metabolic Dysfunction in Polycystic Ovary Syndrome by Activating the Ethe1\/Keap1\/PINK1 Pathway","volume":"21","author":"Xie","year":"2025","journal-title":"Int. J. Biol. Sci."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/371\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:01:13Z","timestamp":1772118073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/3\/371"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ph19030371"],"URL":"https:\/\/doi.org\/10.3390\/ph19030371","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]}}}