Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus Erythematosus - PubMed
6 hours ago
- #Biomarker
- #Systemic Lupus Erythematosus
- #cGAS-STING pathway
- The cGAS-STING pathway is identified as a key driver in systemic lupus erythematosus (SLE).
- A STING-dependent gene signature, M7core, is developed to quantitatively assess cGAS-STING pathway activity in SLE.
- M7core shows widespread activation in 70.4% of 3,180 SLE samples and predicts therapeutic response to STING antagonists in 74.1% of patients.
- M7core outperforms interferon-stimulated gene signatures in diagnostic accuracy (mean AUROC = 0.876) and correlates with disease activity, anti-dsDNA antibodies, lymphopenia, and lupus nephritis.
- Hydroxychloroquine treatment reduces M7core expression and its clinical associations.
- In lupus-like mouse models, STING antagonist administration ameliorates multiorgan pathology and suppresses M7core genes involved in inflammation, type I interferon, and cell death.
- ZBP1 deficiency mimics the effects of blocking the cGAS-STING pathway, highlighting its context-dependent roles in lupus pathogenesis.
- M7core serves as a robust diagnostic and mechanistic biomarker, emphasizing the need to assess pathway activity before STING-targeted therapy in SLE.