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Dunhuang Daxiefei Decoction ameliorates acute lung injury via the HIF-1alpha/glycolysis/H3K18la axis

J Ethnopharmacol. 2026 Mar 26;365:121591. doi: 10.1016/j.jep.2026.121591. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) lacks effective therapies. HIF-1Ξ±-driven glycolysis can promote histone lactylation and sustain pro-inflammatory (M1) macrophage responses. Daxiefei Decoction (DXFD), a classic traditional Chinese medicine formula, is used for pulmonary inflammatory diseases, but its immunometabolic mechanism remains unclear.

AIM OF THE STUDY: To evaluate the protective efficacy of DXFD against lipopolysaccharide (LPS)-induced ALI and to determine whether it acts through the HIF-1Ξ±/glycolysis/histone H3K18 lactylation (H3K18la) axis to regulate macrophage polarization.

MATERIALS & METHODS: DXFD constituents were characterized by UPLC-LTQ-Orbitrap-MS/MS, followed by network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Lung transcriptomics and metabolomics were performed in ALI mice. Efficacy and mechanisms were assessed in LPS-challenged mice and RAW264.7 macrophages using histopathology, ELISA, qRT-PCR, Western blotting, and immunofluorescence. HIF-1Ξ± overexpression was used for validation.

RESULTS: DXFD dose-dependently alleviated lung injury and reduced pro-inflammatory cytokines in vivo, and suppressed M1 polarization in vivo and in LPS-stimulated macrophages. Multi-omics indicated activation of HIF-1Ξ±-associated inflammatory and glycolytic programs in ALI, which were normalized by DXFD. DXFD decreased glycolytic enzyme expression and reduced histone H3K18 lactylation (H3K18la); these effects were partially reversed by HIF-1Ξ± overexpression. Molecular docking and dynamics suggested stable binding of baicalin to HIF-1Ξ±.

CONCLUSIONS: DXFD mitigates ALI by dampening HIF-1Ξ±-dependent glycolysis and H3K18la, thereby restraining M1-driven inflammatory amplification.

PMID:41903585 | DOI:10.1016/j.jep.2026.121591

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