RAC1 as a novel therapeutic target for acute liver failure.

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.