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Toxicarioside H-mediated modulation of the immune microenvironment attenuates ovalbumin-induced allergic airway inflammation by inhibiting NETosis. In the presence of allergens like OVA, neutrophils and other inflammatory cells are recruited, triggering NETosis and the generation of reactive oxygen species (ROS). This process disrupts the balance of immune cells, affecting Th1 and Th2 cells, IL-17 and Treg cells, and memory T cells, thereby promoting allergic asthmatic inflammation. However, ToxH, similar to NEi or NAC, can inhibit NETosis and ROS production, thus modulating the immune environment in allergic asthma and reducing inflammation. [Display omitted] • The novel structural cardiac glycoside, Toxicarioside H (ToxH), effectively inhibits ovalbumin-induced allergic airway inflammation. • ToxH regulates the airway immune microenvironment by maintaining a balance between Th1 and Th2 cells, Th17 and Treg cells, as well as memory T cells. • ToxH mitigates airway inflammation and alters the airway immune microenvironment by suppressing NETosis and reducing ROS production. • Modulating the balance of immune cells in the lung microenvironment with ToxH may represent a promising strategy for treating allergic airway inflammation. Our team identified a new cardiac glycoside, Toxicarioside H (ToxH), in a tropical plant. Previous research has indicated the potential of cardenolides in mitigating inflammation, particularly in the context of NETosis. Therefore, this study sought to examine the potential of ToxH in attenuating allergic airway inflammation by influencing the immune microenvironment. An OVA-induced airway inflammation model was established in BALB/c mice. After the experiment was completed, serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected and further examined using H&E and PAS staining, flow cytometry, immunofluorescence observation, and Western blot analysis. Treatment with ToxH was found to be effective in reducing airway inflammation and mucus production. This was accompanied by an increase in Th1 cytokines (IFN-γ, IL-2, and TNF-β), and the Th17 cytokine IL-17, while levels of Th2 cytokines (IL-4, IL-5, and IL-13) and Treg cytokines (IL-10 and TGF-β1) were decreased in both the bronchoalveolar lavage fluid (BALF) and the CD45+ immune cells in the lungs. Additionally, ToxH inhibited the infiltration of inflammatory cells and decreased the number of pulmonary CD44+ memory T cells, while augmenting the numbers of Th17 and Treg cells. Furthermore, the neutrophil elastase inhibitor GW311616A was observed to suppress airway inflammation and mucus production, as well as alter the secretion of immune Th1, Th2, Th17, and Treg cytokines in the lung CD45+ immune cells. Moreover, our study also demonstrated that treatment with ToxH efficiently inhibited ROS generation, thereby rectifying the dysregulation of immune cells in the immune microenvironment in OVA-induced allergic asthma. Our findings indicate that ToxH could serve as a promising therapeutic intervention for allergic airway inflammation and various other inflammatory disorders. Modulating the balance of Th1/Th2 and Treg/Th17 cells within the pulmonary immune microenvironment may offer an effective strategy for controlling allergic airway inflammation. [ABSTRACT FROM AUTHOR]