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

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.