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Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen
Published on: November 27, 2019
RAC1 as a novel therapeutic target for acute liver failure
Barbara Bueloni1,2,3, Esteban Fiore1,2,4, María José Cantero1,2,4
1Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional, CONICET - Universidad Austral, Av. Pte. Perón 1500, B1629AHJ, Pilar, Buenos Aires, Argentina.
Background & Aims:
The Rho GTPase RAC1 regulates key processes in acute liver failure (ALF), including oxidative stress and inflammation. We aimed to evaluate the therapeutic potential of RAC1 inhibition in ALF.
Methods:
Ingenuity Pathway Analysis and Gene Ontology analysis were performed on transcriptomic datasets from patients with ALF (GSE38941 and GSE80751). ALF was induced in mice using concanavalin A, acetaminophen, or D-galactosamine/lipopolysaccharide (n = 10-21/group). The RAC1 pharmacological inhibitor 1D-142 was used in vivo and in vitro. Hepatocytes and macrophages, from primary cultures and cell lines, were analyzed. RNA-sequencing data from ALF mouse livers (n = 3/group) were integrated with human datasets. Human liver explants (n = 6) were treated in vitro with 1D-142.
Results:
RAC1 emerged as an upstream regulator correlating with immune activation and oxidative stress responses (p <0.05) in human ALF samples. Administration of 1D-142 ameliorated liver injury in murine ALF models when administered at early or late stages post-injury (p <0.05). 1D-142 treatment diminished reactive oxygen species formation (p <0.01), inflammatory cell migration (p <0.001), cytokine production (p <0.05) and hepatocyte death (p <0.05). Liver transcriptomics revealed that RAC1 inhibition modulated key dysregulated pathways in ALF. Human ALF liver explants treated with 1D-142 showed reduced necrosis (p <0.05) and reduced expression of pro-inflammatory genes (p <0.01).
Conclusions:
RAC1 drives sterile inflammation and oxidative stress in ALF. Its pharmacological inhibition protects against liver injury in preclinical models and human explants, supporting RAC1 as a potential therapeutic target in ALF.
Impact And Implications:
Acute liver failure (ALF) is a life-threatening condition characterized by severe inflammation and oxidative stress for which there are limited treatment options. Our study provides strong scientific justification for targeting the RAC1 protein, demonstrating that its pharmacological inhibition with 1D-142 reduces liver injury, immune cell infiltration, and oxidative damage in murine models of ALF and in human liver explants. These findings identify RAC1 as a novel therapeutic target and provide translational support for its potential clinical application in ALF. RAC1-targeted therapy merits further studies in clinical settings.
Insights
Targeting RAC1 (Rho GTPase) protein with 1D-142 effectively reduces liver injury, inflammation, and oxidative stress in acute liver failure (ALF) models. This demonstrates RAC1 inhibition as a promising therapeutic strategy for ALF.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Acute liver failure (ALF) involves severe inflammation and oxidative stress with limited treatments.
- The Rho GTPase RAC1 plays a key role in regulating these pathological processes in ALF.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting RAC1 in ALF.
- To evaluate the efficacy of the RAC1 inhibitor 1D-142 in preclinical ALF models and human liver explants.
Main Methods:
- Transcriptomic analysis of human ALF datasets (GSE38941, GSE80751) and mouse livers.
- Induction of ALF in mice using concanavalin A, acetaminophen, or D-galactosamine/lipopolysaccharide.
- In vivo and in vitro administration of the RAC1 inhibitor 1D-142 to mice, hepatocytes, and macrophages.
- Treatment of human ALF liver explants with 1D-142.
Main Results:
- RAC1 was identified as an upstream regulator correlating with immune activation and oxidative stress in human ALF.
- 1D-142 administration significantly ameliorated liver injury in murine ALF models at various stages.
- RAC1 inhibition reduced reactive oxygen species, inflammatory cell migration, cytokine production, and hepatocyte death.
- 1D-142 treatment decreased necrosis and pro-inflammatory gene expression in human liver explants.
Conclusions:
- RAC1 drives sterile inflammation and oxidative stress in ALF.
- Pharmacological inhibition of RAC1 with 1D-142 demonstrates protective effects against liver injury in preclinical and human models.
- RAC1 represents a potential therapeutic target for ALF, warranting further clinical investigation.
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