International Immunopharmacology · Jun 4, 2025

MOTS-c attenuates airway barrier dysfunction in allergic asthma by inhibiting epithelial apoptosis via Nrf2 pathway

By Zhang W, Li S, Zhang Y et al.

BACKGROUND: Allergic asthma (AA), a severe chronic respiratory disease of chronic airway inflammation, is characterized by bronchial epithelial barrier dysfunction. The MOTS-c/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a protective role in various diseases by reducing inflammatory responses. This study aimed to evaluate the effects of MOTS-c on airway epithelial barrier function in AA. METHODS: MOTS-c levels in the serum of patients with asthma and healthy volunteers were measured by ELISA. C57BL/6 and Nrf2-knockout (Nrf2-/-) mice were stimulated with house dust mites (HDM) to establish an asthma model. Lung tissue injury and mitochondrial function were assessed using hematoxylin and eosin, immunofluorescence, and immunohistochemistry staining. BEAS-2B cells were pretreated using 10 μM MOTS-c for 2 h and then treated with HDM (1 μM) for 24 h. The epithelial barrier and mitochondrial function were detected through western blot and real-time quantitative polymerase chain reaction, respectively. RESULTS: MOTS-c levels were lower in the serum of patients with asthma than in that of healthy volunteers. Exogenous supplementation of MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by HDM. However, MOTS-c reversed the barrier function and mitochondrial damage in AA mice. Furthermore, MOTS-c significantly inhibited inflammation, oxidative stress, and mitochondrial damage in HDM-stimulated BEAS-2B cells. Mechanistically, MOTS-c attenuates airway barrier damage in AA by inhibiting bronchial epithelial apoptosis via the Nrf2 pathway. CONCLUSION: MOTS-c alleviated AA by attenuating airway barrier dysfunction through an Nrf2-dependent mechanism. Therefore, MOTS-c may potentially act as a novel protective agent against AA.

doi.org/10.1016/j.intimp.2025.115014 Open access PubMed 40472776 Interventions