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Here, we characterize the key signature of cGAS\u2010STING pathway and its roles in SLE by leveraging large\u2010scale transcriptomics, cell\u2010based assays, and two lupus\u2010like mouse models. We identify a STING\u2010dependent gene signature termed M7core, enabling quantitative assessment of cGAS\u2010STING pathway activity in SLE. M7core reveals widespread cGAS\u2010STING 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\u2010stimulated gene signatures (mean AUROC = 0.876) and correlates with disease activity, anti\u2010dsDNA antibodies, lymphopenia, and lupus nephritis. Hydroxychloroquine treatment reduces M7core expression and its clinical associations. Importantly, in cGAS\u2010STING pathway\u2010driven lupus\u2010like mice, STING antagonist administration ameliorates multiorgan pathology and suppresses M7core genes participating in promoting inflammation, type I interferon, and cell death, including ZBP1\u2014an established cGAS\u2010STING pathway facilitator. Notably, ZBP1 deficiency phenocopies blocking cGAS\u2010STING pathway\u2010mediated autoimmune pathology exacerbation in pristane\u2010induced lupus\u2010like mice, underscoring its context\u2010dependent 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\u2010targeted therapy in SLE.<\/jats:p>","DOI":"10.1002\/advs.202521560","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:25:20Z","timestamp":1772969120000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrative Analyses Identify a cGAS\u2010STING Pathway\u2010Driven Signature With Context\u2010Dependent Roles in Systemic Lupus Erythematosus"],"prefix":"10.1002","volume":"13","author":[{"given":"Lele","family":"Zhang","sequence":"first","affiliation":[{"name":"Central Laboratory Innovation and Incubation Center Shanghai Pulmonary Hospital School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2010Ju 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