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Updated: Jan 19, 2026
Murine Precision-Cut Liver Slices as an Ex Vivo Model of Liver Biology
Published on: March 14, 2020
PI3K inhibition reduces murine and human liver fibrogenesis in precision-cut liver slices
Emilia Gore1, Emilia Bigaeva1, Anouk Oldenburger2
1Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands.
Background:
Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS).
Methods:
Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 μM for 48 h. PI3K pathway activation was assessed through protein kinase B (Akt) phosphorylation and antifibrotic efficacy was determined via a spectrum of fibrosis markers at the transcriptional and translational level.
Results:
During incubation of PCTS the PI3K pathway was activated and incubation with omipalisib prevented Akt phosphorylation (IC50 = 20 and 1.5 nM for mouse and human, respectively). Viability of mouse and human liver PCTS was compromised only at the high concentration of 10 and 1-5 μM, respectively. However, viability of jejunum PCTS decreased with 0.1 (mouse) and 0.01 μM (human). Spontaneously increased fibrosis related genes and proteins were significantly and similarly suppressed in mouse and in human liver PCTS.
Conclusions:
Omipalisib has antifibrotic properties in ex vivo mouse and human liver PCTS, but higher concentrations showed toxicity in jejunum PCTS. While the PI3K/mTOR pathway appears to be a promising target for the treatment of liver fibrosis, PCTS revealed likely side effects in the intestine at higher doses.
Insights
Omipalisib shows promise in treating liver fibrosis by inhibiting the PI3K/mTOR pathway. However, preclinical models indicate potential intestinal toxicity at higher doses, necessitating careful consideration for therapeutic development.
Area of Science:
- Pharmacology
- Gastroenterology
- Hepatology
Background:
- Liver fibrosis, a significant global health issue, arises from persistent inflammation and injury, with no current approved antifibrotic therapies.
- Omipalisib, a selective PI3K/mTOR pathway inhibitor, has demonstrated in vitro antifibrotic potential.
- Despite ongoing clinical trials for other conditions, a comprehensive preclinical assessment of omipalisib for liver fibrosis is lacking.
Purpose of the Study:
- To evaluate the antifibrotic effects of omipalisib using ex vivo precision-cut tissue slices (PCTS) from murine and human sources.
- To assess the impact of omipalisib on fibrogenesis markers at both transcriptional and translational levels.
- To investigate the potential toxicity of omipalisib in liver and jejunum tissues.
Main Methods:
- Murine and human liver and jejunum PCTS were incubated with omipalisib (up to 10 μM for 48 hours).
- PI3K pathway activation was measured via Akt phosphorylation.
- Antifibrotic efficacy was determined by analyzing a range of fibrosis markers.
Main Results:
- Omipalisib effectively prevented Akt phosphorylation in a dose-dependent manner (IC50 = 20 nM for mouse, 1.5 nM for human liver PCTS).
- Liver PCTS viability was maintained at therapeutic concentrations, but jejunum PCTS showed decreased viability at lower doses (0.1 μM mouse, 0.01 μM human).
- Omipalisib significantly suppressed fibrosis-related genes and proteins in both mouse and human liver PCTS.
Conclusions:
- Omipalisib exhibits antifibrotic properties in ex vivo liver models.
- Potential intestinal toxicity observed at higher concentrations warrants further investigation.
- The PI3K/mTOR pathway is a promising target for liver fibrosis, but careful dose-ranging is crucial to mitigate side effects.
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