The protective effects of Paeoniflorin were completely abolished by co-administration of the TLR4 agonist RS09 TFA.<h4>Conclusion</h4>Paeoniflorin confers protection against sepsis-induced liver injury by modulating macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype through inhibition of the TLR4/NF-κB signaling pathway. The gene discussed is NFKB1; the disease is Sepsis.