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.