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This study comprehensively characterises IFN\u2010I risk gene signatures in SLE. The IFN\u2010I\u2013related genes were obtained from GSE185047, and then Mendelian randomisation analysis using data from the FinnGen cohort (705 SLE cases, 385\u2009509 controls) was utilised as a discovery set to identify IFN\u2010I related risk genes. Single\u2010cell RNA sequencing (scRNA\u2010seq) and external cohorts were used to validate the four key signatures. Univariate and multivariate linear regression models assessed associations between gene expression and clinical parameters. DNA methylation analysis further evaluated epigenetic dysregulation in SLE immune subsets. Thirty\u2010eight IFN\u2010I\u2010related genes were identified, and Mendelian randomisation analysis revealed robust causal associations between four genes (\n                    <jats:italic>HERC5<\/jats:italic>\n                    ,\n                    <jats:italic>IFIT3<\/jats:italic>\n                    ,\n                    <jats:italic>IFI44L<\/jats:italic>\n                    and\n                    <jats:italic>IFI6<\/jats:italic>\n                    ) and SLE risk, with no heterogeneity or pleiotropy. ScRNA\u2010seq demonstrated significant upregulation of these gene signatures in SLE PBMCs and monocytes (except\n                    <jats:italic>IFIT3<\/jats:italic>\n                    in monocytes), along with altered immune cell proportions\u2014specifically, increased monocytes and decreased T cells. External validation confirmed elevated expression of all four genes in SLE, with high diagnostic accuracy. Clinically, increased expression of these genes correlated with SLEDAI, reduced lymphocyte counts and lower complement C4 levels. Furthermore, DNA hypomethylation of\n                    <jats:italic>IFI44L<\/jats:italic>\n                    was observed across multiple SLE immune subsets, indicating epigenetic dysregulation. This study establishes\n                    <jats:italic>HERC5<\/jats:italic>\n                    ,\n                    <jats:italic>IFIT3<\/jats:italic>\n                    ,\n                    <jats:italic>IFI44L<\/jats:italic>\n                    and\n                    <jats:italic>IFI6<\/jats:italic>\n                    as causal IFN\u2010I risk genes in SLE and identifies\n                    <jats:italic>IFI44L<\/jats:italic>\n                    hypomethylation as a key epigenetic driver of IFN\u2010I pathway activation. These findings offer new insights into SLE pathogenesis and highlight potential diagnostic biomarkers and therapeutic targets.\n                  <\/jats:p>","DOI":"10.1111\/exd.70211","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T07:04:36Z","timestamp":1770188676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Comprehensive Analysis of Type I Interferon Risk Gene Signatures in Systemic Lupus Erythematosus"],"prefix":"10.1111","volume":"35","author":[{"given":"Xiangbin","family":"Mi","sequence":"first","affiliation":[{"name":"Department of Dermatology Zhujiang Hospital, Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3957-3709","authenticated-orcid":false,"given":"Kuan","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Dermatology Nanfang Hospital, Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhujiang Hospital, Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology Zhujiang Hospital, Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhujiang Hospital, Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4185-0346","authenticated-orcid":false,"given":"Shanshan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Dermatology Zhujiang Hospital, Southern Medical University  Guangzhou Guangdong 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