A multi-omics approach to decipher the protective mechanism of Myristica fragrans against acute lung injury.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Myristica fragrans Houtt. (Nutmeg) is used in Traditional Chinese Medicine (TCM) to warm the middle energizer and resolve phlegm-dampness, which aligns with the TCM view of Acute Lung Injury (ALI) pathogenesis involving Lung and Spleen dysfunction. AIM OF THE STUDY: This study aimed to systematically decipher the protective effect and molecular mechanism of Myristica fragrans Houtt. (MF) against LPS-induced ALI using a multi-omics strategy. MATERIALS AND METHODS: The protective effect of MF was evaluated in an LPS-induced murine ALI model by assessing inflammatory cytokines and lung histopathology. MF's chemical profile and blood-absorbed components were identified by UHPLC-Q/TOF-MS/MS. Transcriptomics, WGCNA, network pharmacology, and molecular docking were integrated to predict core targets and pathways, which were further validated in LPS-stimulated RAW264.7 macrophages. RESULTS: MF dose-dependently alleviated ALI, reducing TNF-α and IL-6 levels and lung injury, with high-dose efficacy comparable to dexamethasone. Importantly, 3,4-Dimethoxycinnamic acid was first identified from MF and confirmed blood-absorbable. Twenty-four bioactive components (mainly phenolic acids and lignans) were identified in blood. Integrative analysis pinpointed TLR4 and NF-κB as core targets, enriched in TLR4/NF-κB signaling. Molecular docking confirmed their stable binding with key MF components. In vitro, MF suppressed inflammatory mediator release, downregulated iNOS/COX-2, and inhibited the TLR4/NF-κB pathway. CONCLUSIONS: MF protects against LPS-induced ALI by mitigating inflammation. Its bioactive components exert effects through multi-target inhibition of the TLR4/NF-κB pathway, providing a pharmacological basis for its potential use in ALI treatment.