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We compared gene expression profiles from skeletal muscle biopsies between irMyositis patients, patients with spontaneous dermatomyositis (DM, comprising anti-Mi2-positive and anti-TIF1-\u03b3-positive subtypes), and non-diseased controls (NDC). We used the NanoString nCounter PanCancer Immune Profiling Panel to perform differential gene expression (DGE) and pathway enrichment analyses. We identified 93 differentially expressed genes (DEGs) across conditions. Gene set enrichment analysis (GSEA) suggested activation of interferon gamma (type-II IFN) and interferon alpha\/beta (type-I IFN) signaling in irMyositis and DM, respectively. For instance, type-II IFN was upregulated exclusively in irMyositis when compared to DM, which conversely showed upregulation of effector genes downstream type-I IFN. The observed fold-change of a subset of 33 genes drove the GSEA. We further characterized the DEGs using network interaction and expression correlation analyses. This allowed us to describe potential differences between regulatory hubs and cells involved in irMyositis susceptible to ICI effects. For example, the downregulation of <jats:italic>FOXP3<\/jats:italic> we observed together with the upregulation of the chemokine <jats:italic>CCL14<\/jats:italic> in irMyositis may have been a consequence of T cell activation upon ICI therapy. The gene expression correlation and putative molecular interactions set irMyositis apart from DM, particularly with respect to IFN response and DGE of interactors of ICI protein targets (CTLA4, PD-1, PD-L1). Our results suggest new avenues for understanding immunotherapy-related adverse events.<\/jats:p>","DOI":"10.1038\/s41598-025-11944-5","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T17:24:43Z","timestamp":1754328283000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gene expression and molecular pathway analyses differentiate immunotherapy-induced myositis from spontaneous dermatomyositis"],"prefix":"10.1038","volume":"15","author":[{"given":"Magdalena","family":"R\u00f6ckel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Musella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Preusse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefine","family":"Radke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Martin","family":"Thoms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florentia","family":"Dimitriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Endres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"B\u00f6hmerle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waltraud","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Tayb-Boulahfa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Leonard-Louis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Allenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Berking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Stenzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Knauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Vera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Heinzerling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"issue":"Suppl 2","key":"11944_CR1","doi-asserted-by":"publisher","first-page":"S74","DOI":"10.1111\/jns.12339","volume":"24","author":"D Psimaras","year":"2019","unstructured":"Psimaras, D. et al. 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JV has been reimbursed by Novartis for an invited talk. LZ has served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. The other authors report no disclosures relevant to the manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the institutional review boards at the Friedrich-Alexander University Erlangen-N\u00fcrnberg (2_20B), the LMU University Hospital Munich (20-1122) and at the Charit\u00e9 \u2013Universit\u00e4tsmedizin Berlin (EA2\/163\/17). All research was performed in accordance with the legally binding regulations in Germany and the Declaration of Helsinki for research involving human participants. We obtained informed consent from all participants and\/or their legal guardians before handling samples and processing data.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"28434"}}