Semaglutide Reverses Liver Fibrosis in Mice by Activating SIRT1 and Blocking TGF-β/Smad Pathway | Research

The takeaway

Oral semaglutide reduced liver fibrosis in TAA-treated mice by activating SIRT1/p-AMPK, downregulating TGF-β/Smad signaling, reducing α-SMA, and mitigating oxidative stress.

Dual pathway rescue
Semaglutide simultaneously activated the protective SIRT1/AMPK pathway and blocked the fibrosis-driving TGF-β/Smad pathway

What the researchers found

Oral semaglutide (0.12 mg/kg/day) reduced liver fibrosis via SIRT1 activation and TGF-β/Smad downregulation, with reduced α-SMA, improved liver function, and mitigated oxidative stress in TAA-treated mice.

Why it matters

Liver fibrosis affects millions and can progress to cirrhosis and liver cancer. Semaglutide—already widely available—could be repurposed for this devastating condition.

How the study worked

TAA-induced liver fibrosis in mice (150 mg/kg biweekly, 9 weeks), oral semaglutide 0.12 mg/kg daily, assessment of liver function (ALT, AST, GGT, albumin), histopathology, α-SMA, SIRT1, p-AMPK, TGF-β/Smad, and oxidative stress markers.

What this study cannot tell us

Mouse model with chemical-induced fibrosis. Oral dose may not translate directly to human dosing. Single model type tested.

How to read the evidence

Preclinical mouse study with comprehensive pathway analysis. Strong mechanistic evidence supporting repurposing.

When this study was published

Published in 2025.

The bigger picture

Semaglutide's antifibrotic mechanism through SIRT1/AMPK and TGF-β/Smad provides a rationale for treating liver fibrosis regardless of its cause (alcohol, MASH, viral).

Questions still open

Would semaglutide reverse established cirrhosis, not just fibrosis?
Does the SIRT1/TGF-β mechanism apply to human liver fibrosis?
Should semaglutide be trialed specifically for liver fibrosis patients?

Common questions

Can semaglutide treat liver scarring?

In mice, oral semaglutide significantly reduced liver fibrosis by activating protective pathways (SIRT1) and blocking scarring pathways (TGF-β/Smad). Human trials for liver fibrosis are the logical next step.

How does this differ from semaglutide's diabetes effects?

The antifibrotic mechanism (SIRT1/AMPK/TGF-β) is distinct from the appetite and blood sugar effects. This represents a new therapeutic dimension for a drug already taken by millions.

Read the original research

Repurposing of semaglutide by targeting SIRT1 and TGF-β/Smad signaling in hepatic fibrosis.

Naunyn-Schmiedeberg's archives of pharmacology, 399(3), 4413-4425

View on PubMed ↗Publisher’s paper ↗

Citation

Hawary, Omnia A; Wadie, Walaa; El-Said, Yasmin A M; Hassan, Omnia F. (2026). Repurposing of semaglutide by targeting SIRT1 and TGF-β/Smad signaling in hepatic fibrosis.. Naunyn-Schmiedeberg's archives of pharmacology, 399(3), 4413-4425. https://doi.org/10.1007/s00210-025-04675-x