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

ABSTRACT 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.