Commiphora africana Ethanol Extract Attenuates Inflammatory Responses With Reduced NF-κB/AP-1 Activation and Src/TAK1-Related Signaling Changes.

BACKGROUND: The bark, resin, and roots of Commiphora africana (A. Rich.) Engl. have traditionally been used in African medicine to treat fever, stomach disorders, colic, and swelling. However, despite this traditional use, its anti-inflammatory activity and the underlying molecular mechanisms remain poorly characterized.

METHODS: We evaluated the anti-inflammatory activity of C. africana ethanol extract (Caf-EE) in lipopolysaccharide (LPS)-stimulated macrophages and in murine models of HCl/EtOH-induced acute gastric mucosal injury and LPS-induced acute lung injury. Reporter assays, gene expression analysis, immunoblotting, cellular thermal shift assay (CETSA), gas chromatography-mass spectrometry (GC-MS)-guided compound annotation, network pharmacology, and molecular docking were used to investigate the anti-inflammatory mechanisms of Caf-EE.

RESULTS: Caf-EE inhibited nitrite production without cytotoxicity in LPS-stimulated RAW264.7 macrophages. GC-MS-guided feature annotation identified representative candidate constituents of Caf-EE, and network pharmacology indicated their association with inflammation-related pathways. Mechanistically, Caf-EE suppressed MyD88- and TRIF-mediated NF-κB/Activator protein 1 (AP-1) transcriptional activity and reduced the expression of inflammatory genes. Caf-EE also inhibited phosphorylation of Src/IκB kinase (IKK)/IκB- and Transforming growth factor-β-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK)/c-Jun-associated signaling proteins and increased the thermal stability of Src and TAK1. In vivo, Caf-EE attenuated HCl/EtOH-induced acute gastric mucosal injury and LPS-induced acute lung injury, accompanied by reduced phosphorylation of Src and TAK1 in both tissues. Among the representative GC-MS-annotated compounds, 9,19-cyclolanost-24-en-3-ol exhibited the highest predicted binding affinity for Src and TAK1 in molecular docking analysis.

CONCLUSIONS: Collectively, this study provides mechanistic evidence for the anti-inflammatory effects of Caf-EE through modulation of Src/TAK1-associated signaling. Furthermore, the protective effects observed in acute inflammatory disease models support the further development of Caf-EE as a therapeutic candidate for inflammatory disorders.