Triptonide alleviates sepsis‐associated acute lung injury by suppressing the STAT3/HIF‐1α‐mediated aerobic glycolysis in macrophages

Background and Purpose Sepsis‐associated acute lung injury (SA‐ALI), represents a major contributor to mortality among septic patients during the early hyperinflammatory phase. Triptonide, a diterpenoids extract from Tripterygium wilfordii Hook f has anticancer and contraceptive effects. However, its potential and mechanism in SA‐ALI are largely unknown. This study aims to evaluate the therapeutic efficacy and elucidate underlying mechanisms of triptonide in SA‐ALI to identify new clinical strategies. Experimental Approach Lipopolysaccharide (LPS)‐induced endotoxemia model or caecal ligation and puncture (CLP) model was used to induce SA‐ALI in mice, accompanied by treatment with triptonide, triptolide and 2‐methoxyestradiol. Parallel in vitro experiments involved LPS‐treated mouse primary macrophages cultured with or without triptonide. Transcriptomic sequencing of macrophages was performed to explore the anti‐inflammatory mechanisms of triptonide, which were further substantiated using specific activators, inhibitors and adeno‐associated virus (AAV)‐mediated gene targeting. Key Results Our data shows that triptonide effectively inhibits macrophage pro‐inflammatory activation, reduces pulmonary inflammation and alleviates SA‐ALI pathology (i.e. inflammatory cell infiltration, oedema and cell apoptosis), thereby improving the survival of septic mice. Transcriptomic sequencing combined with metabolic analysis shows that triptonide suppresses aerobic glycolysis in pro‐inflammatory macrophages by inhibiting the Signal Transducer and Activator of Transcription 3 (STAT3)/Hypoxia inducible factor‐1α (HIF‐1α) axis. Notably, the therapeutic efficacy of triptonide against SA‐ALI was abolished in myeloid cell‐specific HIF‐1α overexpressed mice (LyzM‐Cre DIO‐ hif1a mice). Conclusions and Implications Triptonide protects against SA‐ALI by suppressing the STAT3/HIF‐1α signalling axis, thereby inhibiting aerobic glycolysis‐mediated pro‐inflammatory macrophage activation, which suggests that triptonide is a promising therapeutic strategy for SA‐ALI.