Inhibition of DDX3X ameliorated CD4+ T cells pyroptosis and improves survival in septic mice

Over-expression of DDX3X mRNA is associated with T cell loss in septic patients. This study aimed to investigate the molecular mechanism of DDX3X on T cell reduction in sepsis. The sepsis model was established using lipopolysaccharide stimulation in vitro and cecal ligation and puncture (CLP) surgery in vivo. Results showed that the expression of DDX3X was significantly upregulated in CD4+ T cells in sepsis. RK-33, the inhibitor of DDX3X, was found to dramatically increase CD4+ T cell counts and prolong the survival rate of mice with sepsis. The results also showed that the expression of caspase-1/GSDMD in CD4+ T cells was significantly increased in vitro and in vivo, and RK-33 can substantially reduce CD4+ T cell pyroptosis through inhibiting NLRP3/caspase-1/GSDMD. Globally, our results suggest that DDX3X is involved in the loss of CD4+ T cells partly through activating the pyroptotic pathway during sepsis, which may provide potential targets for therapeutic interventions in this highly lethal disease.