2. Academic Validation
  3. DNA-PK-mediated phosphorylation of STAT6 establishes a non-canonical type 2 immunity axis to prevent macrophage senescence

DNA-PK-mediated phosphorylation of STAT6 establishes a non-canonical type 2 immunity axis to prevent macrophage senescence

  • Nat Commun. 2026 Feb 24;17(1):3123. doi: 10.1038/s41467-026-69996-8.
Zhao Zhou 1,  Xinmeng Li 1,  Yushuang Wang 1,  Long Liang 2,  Chunyang Wang 1,  Yongchang Sun 3,  Dongmei Wu 4 5,  Yifu Qiu 6 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
  • 2 Department of Respiratory and Critical Care Medicine, Peking University Third Hospital and Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing, China.
  • 3 Department of Respiratory and Critical Care Medicine, Peking University Third Hospital and Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing, China. [email protected].
  • 4 State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China. [email protected].
  • 5 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
  • 6 State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China. [email protected].
  • 7 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
  • 8 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China. [email protected].
PMID: 41735318 DOI: 10.1038/s41467-026-69996-8
Abstract

Macrophage senescence drives inflammaging, a chronic, age-related inflammation. To date, the protective mechanisms against inflammaging are poorly defined. Here, we identify DNA-PK-mediated phosphorylation of murine STAT6 at serine 807 (Ser807) as a crucial post-translational modification for preventing macrophage senescence. Ser807 phosphorylation blocks STAT6 ubiquitination-mediated degradation and promotes STAT6 partnering with PU.1 to activate DNA repair genes. Macrophages lacking Ser807 phosphorylation exhibit DNA repair defects, undergo senescence, and fuel inflammaging. In vivo, the phosphor-null STAT6 mutant (STAT6(S807A)) accelerates macrophage senescence, tissue fibrosis, and systemic aging. Adoptive transfer of phosphomimetic STAT6(S807E)-expressing macrophages rescues accelerated aging. Importantly, phosphorylation of human STAT6 at the homologous residue (Ser817) is significantly reduced in the lungs of patients with chronic obstructive pulmonary disease (COPD), correlating with increased DNA damage and senescence. Thus, our findings reveal a DNA-PK-STAT6 axis enacting a non-canonical type 2 immunity via DNA repair to prevent macrophage senescence, presenting a therapeutic target for healthy aging.

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