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.