Artemetin targets the ABCG2/RAB7A axis to inhibit mitochondrial dysfunction in asthma

Abstract

Background

Artemetin, a natural flavonoid, is well-known for its significant anti-inflammatory and antioxidant properties, but its mechanisms in asthma are still unclear.

Purpose

This study aims to explore the therapeutic potential of Artemetin in mitigating airway inflammation and mitochondrial dysfunction via ABCG2/RAB7A signaling pathway.

Methods

An HDM-induced mouse asthma model and HDM-treated BEAS-2B cell model were established, methods utilized included bioinformatics, molecular docking, Drug Affinity Responsive Target Stability (DARTS), and Cellular Thermal Shift Assay (CETSA), flow cytometry, Western blot, co-immunoprecipitation (CO-IP), immunohistochemistry, and immunofluorescence staining.

Results

Artemetin significantly alleviates the proportion of eosinophils and pro-inflammatory cytokines in BALF, IgE levels in serum, airway epithelial mucus secretion, inflammatory cell infiltration and collagen fiber deposition. ABCG2 was identified as a core binding target of Artemetin. When Artemetin was labeled with Biotin, further experiments confirmed its interaction and upregulation of ABCG2. Overexpression of ABCG2 (OV-ABCG2) enhances antioxidant capacity by upregulating Nrf2, HO-1, SOD and CAT, mitigating mitochondrial oxidative stress (mtROS), improving mitochondrial membrane potential (MMP), and reducing DRP1-mediated mitochondrial fission while enhancing MFN2-mediated fusion. Furthermore, ABCG2 was found to interact with and downregulate RAB7A. Both Artemetin and siRNA-RAB7A notably inhibit p-DRP1 and mitochondrial translocation of DRP1, thereby promoting mitochondrial fusion, reducing mtROS and increasing MMP. KEGG pathway enrichment revealed that ABCG2 is closely linked to apoptosis. Artemetin, OV-ABCG2, and RAB7A knockdown all alleviated HDM-induced PANoptosis by decreasing ZBP1, GSDMD, Caspase-8, FADD, BAX and RIPK1 while increasing anti-apoptotic protein Bcl-2.

Conclusion

Artemetin significantly improves airway inflammation, oxidative stress, and mitochondrial dysfunction in asthma by modulating the ABCG2/RAB7A axis and PANoptosis. Artemetin presents new possibilities for adjunctive therapy in the management of asthma.