Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. Here we show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation and reduced hepatic expression of fibrosis-related and inflammation-related gene pathways. Aptamer-based proteomic analyses of serum samples from patients with MASH in a clinical trial identified 72 proteins significantly associated with MASH resolution and semaglutide treatment, with most related to metabolism and several implicated in fibrosis and inflammation. An independent real-world cohort verified the pathophysiological relevance of this signature, showing that the same 72 proteins are differentially expressed in patients with MASH relative to healthy individuals. Taken together, these data suggest that semaglutide may revert the circulating proteome associated with MASH to the proteomic pattern observed in healthy individuals.
Authors
- Gianluca Mazzoni (ORCID: https://orcid.org/0000-0003-2397-1064)
- Mads Sundby Palle (ORCID: https://orcid.org/0009-0000-7127-2861)
- Jenny Norlin (ORCID: https://orcid.org/0000-0002-4825-6975)
- Rohit S. Loomba (ORCID: https://orcid.org/0000-0002-9116-2835)
- Elisabeth D. Galsgaard (ORCID: https://orcid.org/0000-0002-0584-3803)
- Elisabetta Bugianesi (ORCID: https://orcid.org/0000-0002-0502-4381)
- Philip N. Newsome (ORCID: https://orcid.org/0000-0001-6085-3652)
- Quentin M. Anstee (ORCID: https://orcid.org/0000-0002-9518-0088)
- Kasper Almholt (ORCID: https://orcid.org/0000-0002-9250-514X)
- Lea Mørch Harder (ORCID: https://orcid.org/0009-0007-6126-3380)
- Vlad Ratziu (ORCID: https://orcid.org/0000-0002-6865-3791)
- Kristian Moss Bendtsen (ORCID: https://orcid.org/0009-0005-5914-2972)
- Louise Maymann Nitze
- Kenneth Cusi (ORCID: https://orcid.org/0000-0002-8629-418X)
- Lotte Bjerre Knudsen (ORCID: https://orcid.org/0000-0002-2439-7116)
- Milan Geybels
- Mette Skalshøi Kjær (ORCID: https://orcid.org/0000-0001-6322-4077)
- Vincent Wai‐Sun Wong (ORCID: https://orcid.org/0000-0003-2215-9410)
- Anne‐Sophie Sejling
- Maximilian Jara (ORCID: https://orcid.org/0000-0002-1245-9869)
- Lise Lotte Gluud (ORCID: https://orcid.org/0000-0002-9462-4468)
Institutions
- Inserm (FR)
- King's College - North Carolina (US)
- Chinese University of Hong Kong (HK)
- King's College London (GB)
- Novo Nordisk (Denmark) (DK)
- Hvidovre Hospital (DK)
- University of Florida (US)
- Sorbonne Université (FR)
- University of Oxford (GB)
- Centre de Recherche des Cordeliers (FR)
- Newcastle upon Tyne Hospital (GB)
- NIHR Newcastle Biomedical Research Centre (GB)
- King's College Hospital (GB)
- Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR)
- University of Turin (IT)
- Newcastle University (GB)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-07-21
- DOI
- https://doi.org/10.1038/s41591-025-03799-0
- Citations
- 43
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 58.23
Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Siemens USA
- Gilead Sciences
- Medpace
- Arrowhead Pharmaceuticals
- National Institute for Health and Care Research
- Newcastle University
- European Commission
- Novo Nordisk
- Shionogi
- Genentech
- NIHR Newcastle Biomedical Research Centre