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

The cGAS-STING pathway is emerging as an essential driver in systemic lupus erythematosus (SLE). Here, we characterize the key signature of cGAS-STING pathway and its roles in SLE by leveraging large-scale transcriptomics, cell-based assays, and two lupus-like mouse models. We identify a STING-dependent gene signature termed M7core, enabling quantitative assessment of cGAS-STING pathway activity in SLE. M7core reveals widespread cGAS-STING pathway activation in 70.4% of 3,180 SLE samples and predicts therapeutic response to STING antagonists in 74.1% of patients, with higher activity indicating greater sensitivity. Across ten independent cohorts, M7core outperforms interferon-stimulated gene signatures (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. Importantly, in cGAS-STING pathway-driven lupus-like mice, STING antagonist administration ameliorates multiorgan pathology and suppresses M7core genes participating in promoting inflammation, type I interferon, and cell death, including ZBP1-an established cGAS-STING pathway facilitator. Notably, ZBP1 deficiency phenocopies blocking cGAS-STING pathway-mediated autoimmune pathology exacerbation in pristane-induced lupus-like mice, underscoring its context-dependent roles in lupus pathogenesis. Together, these findings define M7core as a robust diagnostic and mechanistic biomarker and highlight the necessity of assessing pathway activity before initiating STING-targeted therapy in SLE.