KAT8 drives M2 macrophage polarization to exacerbate allergic airway inflammation

Dysregulated macrophage polarization is a pivotal driver of airway inflammation in asthma, yet the underlying molecular mechanisms remain incompletely understood. Here, we demonstrate that histone acetyltransferase KAT8 exacerbates allergic airway inflammation by promoting M2 macrophage polarization in asthma. KAT8 expression was significantly upregulated in lung macrophages of asthmatic mice and in bone marrow-derived macrophages (BMDMs) stimulated with house dust mite (HDM). Macrophage-specific KAT8 deficiency attenuated allergic airway inflammation and inhibited M2 macrophage polarization by suppressing signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, KAT8 directly interacted with STAT3 and targeted it for acetylation, thereby driving M2 macrophage polarization. Importantly, pharmacological inhibition of KAT8 reduced M2 macrophage polarization and attenuated allergic airway inflammation. These findings establish KAT8 as a critical regulator of macrophage-driven allergic inflammation via STAT3 acetylation, highlighting its potential as a therapeutic target for asthma.