USP4-mediated deubiquitination of SRC-1 regulates macrophage polarization and asthma inflammation

Background: Asthma, the most common chronic respiratory disorder affecting individuals of all ages, is driven by inflammation that leads to airway hyperresponsiveness, airway wall remodeling, and mucus production. While inhaled corticosteroids remain the primary treatment despite their limitations, further research into the molecular mechanisms of asthma is needed to identify new therapeutic targets. Methods: A mouse model of asthma was created by treating mice with OVA. HE and PAS staining were used to detect histopathology. Gene and protein expression levels were assessed using qPCR, Western blot, and ELISA. The relationship between USP4 and SRC-1 was examined using Co-IP assay. The ubiquitination levels of SRC-1 were detected using IP assay while macrophage polarization was analyzed by flow cytometry. Results: The ovalbumin-induced mouse model of asthma exhibited a large quantity of inflammatory cell infiltration, proliferation of goblet cells, and increased mucus secretion. SRC-1 expression was upregulated in an OVA-induced mouse model of asthma. Downregulation of SRC-1 reduced macrophage polarization to the M1 phenotype, protecting against OVA-induced asthma, whereas SRC-1 overexpression inhibited M2 macrophage polarization by suppressing the NF-kB signaling pathway. Furthermore, USP4 was found to deubiquitinate SRC-1, enhancing its protein stability. The regulatory axis between USP4 and SRC-1 was validated in vivo. Conclusion: This study demonstrates that USP4 regulates the deubiquitination of SRC-1, which inhibits M2 macrophage polarization and reduces asthma-related inflammation. These findings suggest that USP4 and SRC-1 may serve as potential therapeutic targets for asthma treatment.HighlightsSRC-1 is upregulated in OVA-induced asthma and correlated to macrophage.SRC-1 knockdown reduces M1 macrophage polarization and airway inflammation in the asthma model.SRC-1 overexpression or USP4 overexpression suppresses IL-4-induced M2 polarization via the NF-κB pathway.USP4 regulates the deubiquitination of SRC-1, influencing macrophage polarization and inflammation.