{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T01:55:36Z","timestamp":1790560536152,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0410107"],"award-info":[{"award-number":["JP24ek0410107"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      VEXAS syndrome is a severe X\u2010linked autoinflammatory disorder caused by somatic mutations in ubiquitin\u2010like modifier activating enzyme 1 (\n                      <jats:italic>UBA1<\/jats:italic>\n                      ), with clinical outcomes that vary by\n                      <jats:italic>UBA1<\/jats:italic>\n                      genotype. We aimed to elucidate genotype\u2010specific inflammatory programs and identify potential therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted longitudinal deep phenotyping, including whole blood RNA sequencing (RNA\u2010seq) and clinical activity assessment. Peripheral blood samples were analyzed by single\u2010cell RNA\u2010seq. Human monocytic cell lines harboring each major\n                      <jats:italic>UBA1<\/jats:italic>\n                      mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Thirteen patients with VEXAS syndrome contributed a total of 79 RNA\u2010seq samples. Among genes up\u2010regulated in VEXAS syndrome,\n                      <jats:italic>RNASE1<\/jats:italic>\n                      showed the strongest correlation with longitudinal disease activity (r\u00a0=\u00a00.70, false discovery rate &lt; 0.05) and was up\u2010regulated in patients\u2019 monocytes. In\n                      <jats:italic>UBA1<\/jats:italic>\n                      \u2010mutant monocytic cell lines, genotype\u2010dependent ubiquitination defects were observed in a graded manner (p.Met41Val\u2009&gt; p.Met41Thr\u2009&gt;\u2009p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro\u2010inflammatory cytokine production, progressive cell death, and\n                      <jats:italic>RNASE1<\/jats:italic>\n                      up\u2010regulation, all following the same graded pattern of recapitulating patient genotype\u2013phenotype associations. Transcriptomic analyses demonstrated enrichment of pro\u2010inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor\u2010interacting protein kinase 3 (RIPK3) markedly attenuated all pathologic features, including\n                      <jats:italic>RNASE1<\/jats:italic>\n                      up\u2010regulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our\n                      <jats:italic>UBA1<\/jats:italic>\n                      \u2010mutant monocytic cell\u2010line models, representing three distinct genotypes, recapitulate genotype\u2010dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70332-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70332","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:55:12Z","timestamp":1788778512000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Monocytic Models Reveal Genotype\u2010Dependent Inflammatory Programs in\n                    <scp>VEXAS<\/scp>\n                    Syndrome"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9993-1723","authenticated-orcid":false,"given":"Kana","family":"Higashitani","sequence":"first","affiliation":[{"name":"Department of Stem Cell and Immune Regulation Yokohama City University Graduate School of Medicine  Yokohama Japan"},{"name":"Department of Immunology Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9517-9661","authenticated-orcid":false,"given":"Tatsuma","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Immunology Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9488-661X","authenticated-orcid":false,"given":"Yohei","family":"Kirino","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Immune Regulation Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4915-8134","authenticated-orcid":false,"given":"Go R.","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Immunology Yokohama City University Graduate School of Medicine  Yokohama Japan"},{"name":"Laboratory for Immunotherapy RIKEN Center for Integrative Medical Sciences  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2844-0218","authenticated-orcid":false,"given":"Soichiro","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Immune Regulation Yokohama City University Graduate School of Medicine  Yokohama 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