Mazdutide Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Modulating Endoplasmic Reticulum Stress, Improving Lipid Metabolism and Alleviating Inflammation.

Gan L, Duan L, Zheng X

Pharmaceuticals (Basel, Switzerland)26 Feb 2026

PMID41901218PMCIDPMC13028924DOI10.3390/ph19030371PepBankPUB-41901218

Summary

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 μg/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 < 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-κB)-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/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ) in both models (p Conclusions: Our findings demonstrate that Mazdutide alleviates hepatic ER stress in MASLD, suppresses inflammatory responses and improved lipid metabolism, which ultimately attenuates disease progression.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study18

18 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In mice with diet-induced MASLD, mazdutide ameliorated lipid metabolism disorders compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide improved fat handling compared with untreated mice.
Peptide
Mazdutide
Outcome
Direction not reportedLipid metabolism disorders
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Lipids · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121801
02AnimalAnimal study (in vivo)Efficacy outcome
In mice with diet-induced MASLD, mazdutide reduced liver injury markers compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide lowered liver injury markers compared with untreated mice.
Peptide
Mazdutide
Outcome
DecreaseLiver injury markers
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Liver fat and liver function · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121802
03AnimalAnimal study (in vivo)Efficacy outcome
In mice with diet-induced MASLD, mazdutide reduced hepatic steatosis compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide reduced fat buildup compared with untreated mice.
Peptide
Mazdutide
Outcome
DecreaseHepatic steatosis
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Liver fat and liver function · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121803
04AnimalAnimal study (in vivo)Efficacy outcome
In mice with diet-induced MASLD, mazdutide mitigated inflammation and oxidative stress compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide reduced inflammation and oxidative stress compared with untreated mice.
Peptide
Mazdutide
Outcome
DecreaseInflammation and oxidative stress
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Inflammation markers · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121804
05AnimalAnimal study (in vivo)Mechanism
In mice with diet-induced MASLD, mazdutide alleviated ER stress by modulating the PERK pathway (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide reduced stress in liver cells.
Peptide
Mazdutide
Outcome
DecreaseER stress via PERK pathway
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
Mechanistically, Mazdutide alleviated ER stress by modulating the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121805
06AnimalAnimal study (in vivo)Mechanism
In mice with diet-induced MASLD, mazdutide suppressed the NF-κB-mediated inflammatory response (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide reduced an inflammation pathway.
Peptide
Mazdutide
Outcome
DecreaseNF-κB-mediated inflammatory response
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Inflammation markers · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
suppressed the nuclear Factor kappa B (NF-κB)-mediated inflammatory response
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121806
07AnimalAnimal study (in vivo)Mechanism
In mice with diet-induced MASLD, mazdutide downregulated SREBP-1 expression (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide lowered a fat-making gene regulator.
Peptide
Mazdutide
Outcome
DecreaseSREBP-1 expression
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ)
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121807
08AnimalAnimal study (in vivo)Mechanism
In mice with diet-induced MASLD, mazdutide downregulated C/EBPβ expression (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide lowered a fat-making gene regulator.
Peptide
Mazdutide
Outcome
DecreaseC/EBPβ expression
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ)
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121808
09AnimalAnimal study (in vivo)Mechanism
In mice with diet-induced MASLD, mazdutide downregulated PPARγ expression (p < 0.05).
In plain wordsIn mice with fatty liver, mazdutide lowered a fat-making gene regulator.
Peptide
Mazdutide
Outcome
DecreasePPARγ expression
Study
mousen: not reported in source
High-fat diet-induced MASLD mouse model
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
100, 200, or 400 μg/kg · subcutaneous · 4 weeksAs given in this study (mouse).
Source sentences
Summary
downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ)
1 context sentence(design, population, supporting numbers)
Summary · context
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 μg/kg).
Show in the study text Report a problemFND-4190121809
10LabIn vitro (cells)Efficacy outcome
In hepatocytes with fatty acid-induced steatosis, mazdutide ameliorated lipid metabolism disorders compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide improved fat handling compared with untreated cells.
Peptide
Mazdutide
Outcome
Direction not reportedLipid metabolism disorders
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Lipids · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121810
11LabIn vitro (cells)Efficacy outcome
In hepatocytes with fatty acid-induced steatosis, mazdutide reduced liver injury markers compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide lowered liver injury markers compared with untreated cells.
Peptide
Mazdutide
Outcome
DecreaseLiver injury markers
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Liver fat and liver function · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121811
12LabIn vitro (cells)Efficacy outcome
In hepatocytes with fatty acid-induced steatosis, mazdutide reduced hepatic steatosis compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide reduced fat buildup compared with untreated cells.
Peptide
Mazdutide
Outcome
DecreaseHepatic steatosis
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Liver fat and liver function · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121812
13LabIn vitro (cells)Efficacy outcome
In hepatocytes with fatty acid-induced steatosis, mazdutide mitigated inflammation and oxidative stress compared with the untreated MASLD model group (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide reduced inflammation and oxidative stress compared with untreated cells.
Peptide
Mazdutide
Outcome
DecreaseInflammation and oxidative stress
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Inflammation markers · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
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 < 0.05).
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121813
14LabIn vitro (cells)Mechanism
In hepatocytes with fatty acid-induced steatosis, mazdutide alleviated ER stress by modulating the PERK pathway (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide reduced cell stress.
Peptide
Mazdutide
Outcome
DecreaseER stress via PERK pathway
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
Mechanistically, Mazdutide alleviated ER stress by modulating the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121814
15LabIn vitro (cells)Mechanism
In hepatocytes with fatty acid-induced steatosis, mazdutide suppressed the NF-κB-mediated inflammatory response (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide reduced an inflammation pathway.
Peptide
Mazdutide
Outcome
DecreaseNF-κB-mediated inflammatory response
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Inflammation markers · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
suppressed the nuclear Factor kappa B (NF-κB)-mediated inflammatory response
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121815
16LabIn vitro (cells)Mechanism
In hepatocytes with fatty acid-induced steatosis, mazdutide downregulated SREBP-1 expression (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide lowered a fat-making gene regulator.
Peptide
Mazdutide
Outcome
DecreaseSREBP-1 expression
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121816
17LabIn vitro (cells)Mechanism
In hepatocytes with fatty acid-induced steatosis, mazdutide downregulated C/EBPβ expression (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide lowered a fat-making gene regulator.
Peptide
Mazdutide
Outcome
DecreaseC/EBPβ expression
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121817
18LabIn vitro (cells)Mechanism
In hepatocytes with fatty acid-induced steatosis, mazdutide downregulated PPARγ expression (p < 0.05).
In plain wordsIn lab tests on fatty liver cells, mazdutide lowered a fat-making gene regulator.
Peptide
Mazdutide
Outcome
DecreasePPARγ expression
Study
n: not reported in source
Hepatocytes treated with 1 mM free fatty acids for 24 h
Comparator
MASLD model group
Outcome group
Receptor activity and mechanism · Liver
Studied dose
10, 20, or 50 nMAs given in this study.
Source sentences
Summary
downregulated the expression of key lipogenic regulators including sterol regulatory element-binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein beta (C/EBPβ), and peroxisome proliferator-activated receptor gamma (PPARγ)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-4190121818

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
9 Oct 2026, 18:17 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

Publication types

Keywords

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