KAT8-mediated PCBP1 acetylation drives neutrophil recruitment in papain-induced airway inflammation

Macrophages play central role in driving airway inflammation during asthma pathogenesis, though the molecular mechanism governing their function remains incompletely understood. Here, we demonstrate that lysine acetyltransferase 8 (KAT8) plays a critical role in papain-induced neutrophilic airway inflammation through post-translational modification of poly(C)-binding protein 1 (PCBP1). We show that papain exposure significantly upregulates KAT8 expression in lung macrophages both in vivo and in vitro. Myeloid-specific Kat8 deficiency conferred protection against papain-induced airway inflammation, reducing CXCL1 and CXCL2 production and consequent neutrophil recruitment. Mechanistically, KAT8 interacted with PCBP1 via its C2HC zinc finger domain and acetylated it at lysine 119 (K119), an essential modification for CXCL1 and CXCL2 secretion. Moreover, KAT8 enhanced M1 macrophage polarization in papain-exposed mice. Importantly, pharmacological inhibition of KAT8 significantly attenuated neutrophil infiltration and allergic airway inflammation in vivo. Our findings establish KAT8 as a pivotal regulator of neutrophilic airway inflammation through PCBP1 acetylation and highlight the KAT8-PCBP1 axis as a promising therapeutic target for severe asthma.