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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Data availability
This paper does not report original code. The original RNA-seq datasets of Thio-PMs is available from GEO (GSE278458, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE278458). The ChIP-seq dataset of macrophages (PU.1) are obtained from GSE38377 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository with the dataset identifier PXD074331. All materials generated in this study, including stable cell lines and newly developed pSTAT6 antibodies for mouse and human, will be made available upon request. Source data are provided in this paper.
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Acknowledgements
We thank members of the Qiu laboratory for comments on the manuscript. We are grateful to the Flow Cytometry Core of the National Center for Protein Sciences and the Core Facilities of Life Sciences at Peking University for assistance with flow cytometry and confocal microscopy. We also thank Ms. Meng Han in the Proteomics Facility at Tsinghua University Technology Center for Protein Sciences for mass spectrometry analysis of protein modification. This work was supported by grants from the National Key R&D Program of the Ministry of Science and Technology of the People’s Republic of China (2024YFA1802103, 2021YFA0804801 and 2018YFA0800702) to Y.Q.
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Z.Z. designed and performed the main experiments with assistance from X.L., Y.W., L.L., C.W., Z.Z., Y.S., D.W., and Y.Q. discussed and interpreted the results from the study; Z.Z., D.W., and Y.Q. conceived, supervised, and wrote the paper.
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Zhou, Z., Li, X., Wang, Y. et al. DNA-PK-mediated phosphorylation of STAT6 establishes a non-canonical type 2 immunity axis to prevent macrophage senescence. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69996-8
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DOI: https://doi.org/10.1038/s41467-026-69996-8
