A new study has explored the underlying mechanisms by which semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), improves outcomes in patients with metabolic dysfunction-associated steatohepatitis (MASH).¹ The research, which combined analysis of a phase 2 clinical trial with preclinical models, identified a unique proteomic signature associated with treatment and suggests that semaglutide’s benefits extend beyond weight loss alone.
This study utilised data and biosamples from a 72-week, phase 2, randomised, placebo-controlled trial (NCT02970942).² The trial included 320 adults with biopsy-confirmed MASH and liver fibrosis stages 1–3. Participants received once-daily subcutaneous semaglutide (0.1 mg, 0.2 mg, or 0.4 mg) or placebo.
Researchers performed a mediation analysis to determine the contribution of weight loss to histological improvements. They also conducted aptamer-based proteomic profiling (SomaScan) on serum samples to identify proteins associated with MASH resolution and semaglutide treatment. These findings were validated against an independent real-world cohort. Additionally, two preclinical mouse models of MASH were used to investigate the effects of semaglutide on hepatic gene expression.¹
Mediation analysis confirmed that weight loss was a substantial driver of MASH resolution, mediating 69.3% of the total treatment effect. However, its contribution to the improvement in liver fibrosis was less pronounced (25.1%), indicating that other mechanisms are also at play.¹
Proteomic analysis of nearly 5,000 proteins identified a ‘treatment signature’ of 72 unique proteins that were significantly associated with both MASH resolution and semaglutide treatment. In an independent cohort, these same 72 proteins were differentially expressed in patients with MASH compared to healthy individuals. The changes observed with semaglutide treatment appeared to reverse the MASH-associated protein profile towards that seen in healthy controls.¹
Preclinical data supported these findings, showing that semaglutide reduced the hepatic expression of genes related to fibrosis and inflammation. Furthermore, the study confirmed the absence of GLP-1 receptors on key liver cells, including hepatocytes, in both human and mouse tissue, supporting an indirect, extrahepatic mechanism of action.¹
This research provides significant insight into how semaglutide exerts its beneficial effects in MASH. While weight loss is the predominant mediator for improving disease activity, the findings suggest that semaglutide also modulates distinct metabolic, inflammatory, and fibrotic pathways. The identification of a 72-protein signature not only deepens the understanding of the drug’s biological impact but also highlights potential biomarkers for disease and treatment response. The study authors concluded that "semaglutide may revert the circulating proteome associated with MASH to the proteomic pattern observed in healthy individuals."¹
The ongoing phase 3 ESSENCE trial (NCT04822181) will provide further clarity on the histological efficacy of semaglutide in MASH, including its effects on fibrosis improvement.
References
1. Jara M, Norlin J, Kjær MS, et al. Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis. Nat Med. 2025. https://doi.org/10.1038/s41591-025-03799-0
2. Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113–1124. https://doi.org/10.1056/NEJMoa2028395
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