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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

Targeting Macrophage STING O-GlcNAcylation via Small-Molecule Allosteric Modulation for Psoriasis Therapy.

  • Fang-Fang Zhuo1
  • Cheng-Chen Hou1
  • Wei Wang1
  • Ya-Xuan Zhu1
  • Ling Li1
  • Li-Juan Liu2
  • Chuan-Jian Lu2
  • Peng-Fei Tu1
  • Yang Liu3
  • Rui-Zhi Zhao2
  • Ke-Wu Zeng1,4,5
5 affiliations
  1. 1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  2. 2State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  3. 3Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
  4. 4Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.
  5. 5Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital, Beijing, China.
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Abstract

STING undergoes distinct post-translational modifications in autoimmune disorders, particularly in psoriasis. However, selectively targeting these disease-associated STING modifications remains a major therapeutic challenge. Here, we show that macrophage STING O-GlcNAcylation is a critical driver of psoriatic inflammation and identify the natural small-molecule paeoniflorin (PF) as a selective inhibitor of STING O-GlcNAcylation. Mechanistically, PF engages the cyclic dinucleotide-binding domain (CBD) of STING, inducing an allosteric conformational shift that traps STING in an inactive open state. This allosteric mechanism sterically blocks O-GlcNAc transferase (OGT) recruitment to STING, thereby suppressing STING O-GlcNAcylation and subsequent TBK1-dependent phosphorylation cascades. In vivo, PF markedly alleviates psoriatic skin inflammation, whereas myeloid-specific STING ablation substantially compromises its therapeutic efficacy. Critically, clinical analyses of patient-derived samples further support the relevance of STING O-GlcNAcylation to psoriasis. Together, our work uncovers macrophage STING O-GlcNAcylation as a critical regulatory checkpoint in psoriatic inflammation, highlighting a promising natural product-based strategy for targeting pathological STING signaling.

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Cite

BibTeXRIS
BibTeX
@article{zhuo2026targeting,
  title = {{Targeting Macrophage STING O-GlcNAcylation via Small-Molecule Allosteric Modulation for Psoriasis Therapy.}},
  author = {Fang-Fang Zhuo and Cheng-Chen Hou and Wei Wang and Ya-Xuan Zhu and Ling Li and Li-Juan Liu and Chuan-Jian Lu and Peng-Fei Tu and Yang Liu and Rui-Zhi Zhao and Ke-Wu Zeng},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78257},
  url = {https://europepmc.org/article/MED/42875819},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Targeting Macrophage STING O-GlcNAcylation via Small-Molecule Allosteric Modulation for Psoriasis Therapy.
AU  - Fang-Fang Zhuo
AU  - Cheng-Chen Hou
AU  - Wei Wang
AU  - Ya-Xuan Zhu
AU  - Ling Li
AU  - Li-Juan Liu
AU  - Chuan-Jian Lu
AU  - Peng-Fei Tu
AU  - Yang Liu
AU  - Rui-Zhi Zhao
AU  - Ke-Wu Zeng
PY  - 2026
DA  - 2026/10/14
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78257
UR  - https://europepmc.org/article/MED/42875819
AB  - STING undergoes distinct post-translational modifications in autoimmune disorders, particularly in psoriasis. However, selectively targeting these disease-associated STING modifications remains a major therapeutic challenge. Here, we show that macrophage STING O-GlcNAcylation is a critical driver of psoriatic inflammation and identify the natural small-molecule paeoniflorin (PF) as a selective inhibitor of STING O-GlcNAcylation. Mechanistically, PF engages the cyclic dinucleotide-binding domain (CBD) of STING, inducing an allosteric conformational shift that traps STING in an inactive open state. This allosteric mechanism sterically blocks O-GlcNAc transferase (OGT) recruitment to STING, thereby suppressing STING O-GlcNAcylation and subsequent TBK1-dependent phosphorylation cascades. In vivo, PF markedly alleviates psoriatic skin inflammation, whereas myeloid-specific STING ablation substantially compromises its therapeutic efficacy. Critically, clinical analyses of patient-derived samples further support the relevance of STING O-GlcNAcylation to psoriasis. Together, our work uncovers macrophage STING O-GlcNAcylation as a critical regulatory checkpoint in psoriatic inflammation, highlighting a promising natural product-based strategy for targeting pathological STING signaling.
SN  - 2198-3844
ER  -