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Integrative Analyses Identify a cGAS-STING Pathway-Driven Signature With Context-Dependent Roles in Systemic Lupus

Lele Zhang1, Ming-Ju Amy Lyu1,2, Ze Hong3

  • 1Central Laboratory, Innovation and Incubation Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

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Summary
This summary is machine-generated.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial in systemic lupus erythematosus (SLE). A new M7core gene signature quantifies pathway activity, aiding diagnosis and predicting STING antagonist therapy response in SLE patients.

Keywords:
Sting−/− miceTrex1−/− miceZbp1−/− micepristine‐induced lupus‐like micesystemic lupus erythematosusthe cGAS‐STING pathway

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Area of Science:

  • Immunology
  • Genetics
  • Rheumatology

Background:

  • The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is increasingly recognized as a key factor in systemic lupus erythematosus (SLE) pathogenesis.
  • Understanding the precise role and activity of this pathway is critical for developing targeted therapies.

Purpose of the Study:

  • To characterize the cGAS-STING pathway signature in SLE.
  • To develop a quantitative biomarker for assessing cGAS-STING pathway activity.
  • To evaluate the predictive value of this biomarker for therapeutic response to STING antagonists.

Main Methods:

  • Leveraged large-scale transcriptomics, cell-based assays, and two lupus-like mouse models.
  • Identified a STING-dependent gene signature (M7core) for quantitative assessment of cGAS-STING pathway activity.
  • Validated M7core across ten independent cohorts and compared it with interferon-stimulated gene signatures.

Main Results:

  • Identified M7core, a STING-dependent gene signature, enabling quantitative assessment of cGAS-STING pathway activity in SLE.
  • M7core showed widespread activation in 70.4% of SLE samples and predicted therapeutic response to STING antagonists in 74.1% of patients.
  • M7core outperformed existing signatures, correlated with disease activity markers, and was reduced by hydroxychloroquine treatment.
  • STING antagonist administration ameliorated pathology in mouse models, suppressing M7core genes, including ZBP1, a key facilitator.

Conclusions:

  • M7core serves as a robust diagnostic and mechanistic biomarker for cGAS-STING pathway activity in SLE.
  • Assessing cGAS-STING pathway activity is essential for guiding STING-targeted therapy selection in SLE patients.
  • ZBP1 plays context-dependent roles in lupus pathogenesis, highlighting its significance in cGAS-STING-mediated inflammation.