SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis

-dependent deacetylase Sirtuin 6 (SIRT6) regulates immune responses, its role in neutrophilic asthma remains unknown. Utilizing multiple human samples and neutrophilic asthma murine model, we identify macrophage SIRT6 as a key regulator that governs airway neutrophil infiltration in severe asthma. Myeloid-specific Sirt6 deletion attenuates allergen-induced airway neutrophil infiltration by suppressing lactate dehydrogenase A (LDHA)-mediated lactate production and neutrophil-recruiting chemokines secretion. Mechanistically, SIRT6 directly interacts with LDHA and deacetylates LDHA at lysine 261 (K261) via SIRT6-N-terminal domain. Lactate accumulation promotes histone H4 lysine 12 (H4K12) lactylation, up-regulating Cxcl1 and Cxcl2 transcription to drive airway neutrophil infiltration. Importantly, we screen flavonoid astragalin as a specific SIRT6 inhibitor that attenuates airway neutrophil infiltration in severe asthmatic mice. Collectively, our findings reveal a critical role of the SIRT6-mediated metabolic reprogramming in neutrophilic asthma and establish SIRT6 as a promising therapeutic target.