SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis
- Cell Rep. 2026 May 26;45(5):117294. doi: 10.1016/j.celrep.2026.117294.
- 1. Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China; Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
- 2. Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan 523808, China.
- 3. School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang 524023, China.
- 4. Department of Geriatrics, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.
- 5. Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
- 6. Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
- 7. The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang 524023, China.
- 8. Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China. Electronic address: [email protected].
- 9. Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China; Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China. Electronic address: [email protected].
- 10. Institute of Respiratory Diseases, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China. Electronic address: [email protected].
- 11. Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China; Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China. Electronic address: [email protected].
Neutrophilic asthma is a steroid-resistant condition linked to immunometabolic dysregulation. While the NAD+-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.
-
Cat. No.Product NameDescriptionTargetResearch Area
-