Baicalein attenuates acute liver injury by blocking NLRP3 inflammasome

Infection and/or drug-mediated acute liver injury, the leading cause of lethal liver failure, is a critical health problem worldwide and lacks effective treatment. Here, we used Lipopolysaccharides (LPS)/D-galactosamine (D-gal)-treated primary hepatocytes to screen a natural library that contains 1130 chemicals. Baicalein in the library showed highest inhibitory effects against LPS/D-Gal-induced liver injury. In-vivo study similarly validated the protection of baicalein against dampened liver function and increased lethality after a challenge of LPS/D-Gal. Using a cytometric bead array, we found that IL-1 alpha and IL-1 beta, the downstream of NLRP3, had highest reduction among the plasma inflammatory cytokines in LPS/D-Gal-challenged mice after a treatment of baicalein. To determine the target of baicalein and the underlying mechanism, NIrp3(-/-), Gsdmd(-/-) or WT mice were treated with or without baicalein, IL-1R antibody or recombinant mouse IL-1 beta (rmIL-1 beta) prior to a challenge of LPS/D-Gal. Deficiency of NIrp3 or Gsdmd significantly restored LPS/D-Gal-induced acute liver injury and lethality, and further administration of baicalein did not have additive effects. In addition, the inhibition of the downstream by IL-1R antibody phenocopied the knockout of NIrp3 or Gsdmd. Moreover, a challenge of rmIL-1 beta reversed the improvement in NIrp3(-/-) mice or the mice treated with baicalein. Taken together, NLRP3 functions as a pivotal promoter in acute liver injury and baicalein attenuates acute liver injury by inhibiting NLRP3 inflammasome. (C) 2020 Elsevier Inc. All rights reserved.

Automated summary

The study found that baicalein alleviates infection and/or drug-induced acute liver injury by inhibiting NLRP3 inflammasome, suggesting its potential therapeutic value.