Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation.

Exercise can enhance the body's ability to resist infections, but its molecular mechanisms are still unclear. Here, we found that exercise can induce a hyperactivation-like state of the NLRP3 inflammasome during infection, which enhances the body's ability to resist infection by continuously secreting inflammatory cytokines and reducing immune cell pyroptosis. At the molecular level, exercise enhances the binding between CNDP2 and GSDMD, promoting the production of γ-Glu-Cys. γ-Glu-Cys binds to CypD and inhibits the binding between CypD and GSDMD, thereby avoiding further damage to the mitochondrial inner membrane during the occurrence of inflammasomes. Limited mitochondrial DNA leakage allows the NLRP3 inflammasome to a hyperactivate state. Our findings reveal the molecular mechanisms by which exercise enhances the body's ability to resist infections, and provide possible standards for better guiding exercise intensity to improve anti-infection capabilities in the future.