Targeting RAC1 as a novel strategy to reduce inflammation and liver damage in acute liver failure.
Background & Aims: The Rho GTPase RAC1 regulates key drivers of acute liver failure (ALF) such as oxidative stress and inflammation. The goal of this study was to determine the therapeutic potential of RAC1 pharmacological inhibition in ALF. Methods: The involvement of RAC1 in human ALF was explored by analyzing public transcriptome datasets. Murine models of ALF were induced by administration of either Concanavalin A, acetaminophen or D-Galactosamine/Lipopolysaccharide. In vitro assays were conducted on hepatocytes and macrophages primary cultures and cell lines. 1D-142 was used to explore the effect of RAC1 pharmacological inhibition. RNA-Seq analysis was performed and correlated with ALF human datasets to explore the therapeutic potential of RAC1 inhibition. Liver explants from patients with liver failure were treated in vitro with 1D-142. Results: RAC1-related pathways are upregulated in human ALF samples and correlate with immune activation and oxidative stress. Administration of 1D-142 ameliorated liver damage across all ALF murine models. 1D-142 treatment diminishes reactive oxygen species formation and reduces inflammatory cells migration and suppresses cytokine production both in vivo and in vitro. Transcriptome analysis of treated livers indicates that RAC1 pharmacological inhibition modulates dysregulated biological processes observed in ALF patients. Liver explants from ALF patients treated with 1D-142 exhibited reduced necrosis and reduced expression of pro-inflammatory genes. Conclusions: RAC1 plays a critical role in driving inflammation and oxidative stress in ALF. Targeted inhibition of RAC1 with 1D-142 protects against ALF in murine models; thus, RAC1 inhibition could be a potential therapeutic option for ALF. Overall design: Transcriptomic Profiling of C57BL/6J Mouse Livers During Acute Liver Failure Induced by acetaminophen or concanavalin A and Treated with the RAC1 Inhibitor 1D-142