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Publications

Journal Article Epublish

PubMed: 41098236 DOI: 10.1016/j.jhepr.2025.101547

RAC1 as a novel therapeutic target for acute liver failure.

JHEP Rep 7(11):101547

Authors: Barbara Bueloni, Esteban Fiore, María José Cantero, Lucia Lameroli, Catalina Atorrasagasti, Matías Ciarlantini, Andrea Barquero, Lucía Gandolfi Donadio, Daiana Ganiewich, Francisco Orozco, Martín Fauda, Julieta Comin, Ali Canbay, Juan Bayo, Guillermo Mazzolini

Affiliations

  • Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional, CONICET - Universidad Austral, Av. Pte. Perón 1500, B1629AHJ, Pilar, Buenos Aires, Argentina.
  • Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Perón 1500, B1629AHJ, Pilar, Buenos Aires, Argentina.
  • HZ4 Liver Inc./Spectrum, Dover, DE, USA.
  • Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
  • Departamento de Ingredientes Activos y Biorrefinerías, Instituto Nacional de Tecnología Industrial, Av. General Paz 5445, San Martin, Buenos Aires, Argentina.
  • Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, Argentina.
  • Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Ciudad Universitaria, Ciudad Autónoma de Buenos Aires, Argentina.
  • Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. Departamento de Ingredientes Activos y Biorrefinerías, Instituto Nacional de Tecnología Industrial, Av. General Paz 5445, San Martin, Buenos Aires, Argentina.
  • Fundación Instituto Leloir - CONICET, Buenos Aires, Argentina.
  • Hepatobiliary Surgery and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina.
  • Department of Internal Medicine, Ruhr-Universitat Bochum, Bochum, Germany.
  • Liver Unit, Hospital Universitario Austral, Universidad Austral, Av. Pte. Perón 1500, Pilar B1629AHJ, Argentina.

Abstract

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.

MeSH

Cells, Genes, Hepatocytes, Stress, Physiological, Oxidative Stress, Liver, Liver Failure, Acute, Therapeutics, Liver Failure