OBJECTIVE To investigate how tubeimoside III inhibits lipopolysaccharide(LPS)-induced inflammatory responses by reprogramming glucose metabolism. METHOD A mouse model of LPS-induced acute inflammation was constructed, and the protective effect of tubeimoside III against LPS-induced injury was investigated using histochemistry and real-time quantitative PCR. Western blotting, Seahorse extracellular flux analyser assays, and pyruvate content assays were used in LPS-induced RAW264.7 cells to explore how tubeimoside III exerts its anti-inflammatory effects. The potential mechanism was also validated using inhibitors. RESULTS Tubeimoside III significantly attenuated the expression of inflammatory cytokines IL-6, IL-1β, and iNOS in lung and liver tissue homogenates and RAW264.7 cells. This agent inhibited inflammatory cell infiltration in alveoli and prevented necrosis in liver lesions in LPS-treated mice. Extracellular flux analyser assays revealed that tubeimoside III regulated glucose metabolism in RAW264.7 cells. Real-time quantitative PCR and western blot revealed that tubeimoside III had similar effects on the downstream effector molecule of itaconic acid. An inhibitor weakened the inhibitory effect of tubeimoside III on the expression of inflammatory factors. CONCLUSIONS Tubeimoside III protects against LPS-induced lung and liver injury by attenuating inflammatory factor secretion and inflammatory cell infiltration, and its mechanism of action involves reprogramming macrophage glucose metabolism and increasing itaconic acid levels.