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Updated: Feb 26, 2026

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

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Fosforilación de STAT6 mediada por DNA-PK establece un eje de inmunidad tipo 2 no canónico para prevenir la

Zhao Zhou¹, Xinmeng Li¹, Yushuang Wang¹

¹State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.

Nature communications

|February 24, 2026

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.

Palabras clave:

DNA-PK STAT6 senescencia de macrófagos inflamación reparación del ADN envejecimiento inmunidad tipo 2 enfermedades relacionadas con la edad COPD

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