International immunopharmacology · 2026
Celastrol alleviates LPS-induced acute lung injury by suppressing neutrophilic inflammation burst through targeting AKT.
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Zhang Yu, Yang Yun, Lin Zhifeng, Chen Riken, Qiang Xinhua, Li Chang, Guo Weiguang, Cao Jun, Ye Yinong, Zhou Lixin
Аннотация
BACKGROUND: Acute lung injury (ALI) is a severe, life-threatening inflammatory condition, characterized by uncontrolled neutrophilic inflammation and tissue damage. That emphasized the urgent need for innovative pharmacologic therapies. The aim of this study was to investigate the effects of Celastrol, a major bioactive compound extracted from the Thunder of God Vine, and the underlying mechanisms of its impact on ALI.
METHODS: In this study, the effects of Celastrol on ALI were assessed using a lipopolysaccharide (LPS)-induced ALI model in C57BL/6 mice. Integrated network pharmacology and transcriptomics (RNA-seq) were utilized to screen for potential therapeutic targets. Furthermore, neutrophil functions, including respiratory burst, degranulation, chemotaxis, and neutrophil extracellular traps (NETs) formation, were assessed. The release of NETs was quantified by MPO-DNA complex ELISA. Crucially, experiments using the specific AKT activator SC79 were performed to validate the functional dependency on the AKT signaling pathway.
RESULTS: Our results revealed that Celastrol exerted protective effects against LPS-induced ALI by reducing alveolar-capillary membrane dysfunction and suppressing neutrophil recruitment and activation. Multi-omics analysis indicated AKT as a pivotal target of Celastrol. Venn diagram analysis further identified 10 core consensus targets between network pharmacology and transcriptomics, including AKT1. Molecular docking revealed a high binding affinities between Celastrol and AKT1, AKT2 and AKT3, which was corroborated by kinase assays showing that Celastrol potently inhibited AKT kinase activity. Western blotting further confirmed this specific targeting, demonstrating that Celastrol decreased the phosphorylation of AKT (Ser473 and Thr308) without affecting the upstream PI3K. Furthermore, Celastrol suppressed LPS-induced neutrophil activation, evidenced by reduced ROS production, elastase release, chemotaxis, and NETs formation. Mechanistically, Celastrol inhibited NETs formation via the PAD4/citH3 axis and suppressed chemotaxis through the FAK/Rac1/Cdc42 pathway. Notably, the AKT activator SC79 significantly reversed these inhibitory effects, confirming that Celastrol mitigates neutrophil activation and NETs formation primarily by targeting AKT.
CONCLUSION: Celastrol has the potential to be developed as a therapeutic candidate for LPS-induced ALI by targeting AKT to inhibit neutrophil respiratory burst, degranulation, chemotaxis and NETs formation. These findings provide novel mechanistic insights into the immunomodulatory action of Celastrol, although its clinical application requires further validation.
METHODS: In this study, the effects of Celastrol on ALI were assessed using a lipopolysaccharide (LPS)-induced ALI model in C57BL/6 mice. Integrated network pharmacology and transcriptomics (RNA-seq) were utilized to screen for potential therapeutic targets. Furthermore, neutrophil functions, including respiratory burst, degranulation, chemotaxis, and neutrophil extracellular traps (NETs) formation, were assessed. The release of NETs was quantified by MPO-DNA complex ELISA. Crucially, experiments using the specific AKT activator SC79 were performed to validate the functional dependency on the AKT signaling pathway.
RESULTS: Our results revealed that Celastrol exerted protective effects against LPS-induced ALI by reducing alveolar-capillary membrane dysfunction and suppressing neutrophil recruitment and activation. Multi-omics analysis indicated AKT as a pivotal target of Celastrol. Venn diagram analysis further identified 10 core consensus targets between network pharmacology and transcriptomics, including AKT1. Molecular docking revealed a high binding affinities between Celastrol and AKT1, AKT2 and AKT3, which was corroborated by kinase assays showing that Celastrol potently inhibited AKT kinase activity. Western blotting further confirmed this specific targeting, demonstrating that Celastrol decreased the phosphorylation of AKT (Ser473 and Thr308) without affecting the upstream PI3K. Furthermore, Celastrol suppressed LPS-induced neutrophil activation, evidenced by reduced ROS production, elastase release, chemotaxis, and NETs formation. Mechanistically, Celastrol inhibited NETs formation via the PAD4/citH3 axis and suppressed chemotaxis through the FAK/Rac1/Cdc42 pathway. Notably, the AKT activator SC79 significantly reversed these inhibitory effects, confirming that Celastrol mitigates neutrophil activation and NETs formation primarily by targeting AKT.
CONCLUSION: Celastrol has the potential to be developed as a therapeutic candidate for LPS-induced ALI by targeting AKT to inhibit neutrophil respiratory burst, degranulation, chemotaxis and NETs formation. These findings provide novel mechanistic insights into the immunomodulatory action of Celastrol, although its clinical application requires further validation.