{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:19:56Z","timestamp":1788484796057,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371815"],"award-info":[{"award-number":["82371815"]}],"id":[{"id":"10.13039\/501100001809","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>To explore the clinical relevance of mitochondrial DNA (mtDNA) in systemic sclerosis (SSc) and elucidate the mechanism by which mtDNA leakage drives fibroblast activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Plasma mtDNA was quantified by quantitative polymerase chain reaction in 50 patients with SSc and 20 healthy controls (HCs). Primary dermal fibroblasts from five patients with diffuse cutaneous SSc and five HCs (n\u00a0=\u00a05 per group) were analyzed for mitochondrial structure, function, and RNA sequencing profiling. The opening of the mitochondrial permeability transition pore (mPTP) and oligomerization of VDAC1 were examined with Ca\n                      <jats:sup>2+<\/jats:sup>\n                      modulators and inhibitors. Stimulator of interferon genes (STING) knockdown using small interfering RNA was performed for validation. The STING inhibitor H\u2010151 was evaluated in vitro and in a bleomycin\u2010induced skin fibrosis model (n\u00a0=\u00a06 mice per group).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Plasma mtDNA levels were significantly higher in patients with SSc than in HCs, negatively correlating with forced vital capacity (r\u00a0=\u00a0\u22120.436,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.01) and positively correlating with the modified Rodnan skin score (r\u00a0=\u00a00.807,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), interleukin\u20106 (r\u00a0=\u00a00.667,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), and transforming growth factor \u03b2 (r\u00a0=\u00a00.678,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001). SSc fibroblasts exhibited abnormal mitochondrial morphology and dysfunction. Increased MCU and VDAC1 levels promoted mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload, mPTP opening, VDAC1 oligomerization, and cytosolic mtDNA accumulation, which activated the cyclic GMP\u2010AMP synthase (cGAS)\u2013STING pathway and triggered profibrotic responses. Pharmacologic blockade of mPTP or VDAC1 reduced cytosolic mtDNA, whereas H\u2010151 suppressed profibrotic markers in SSc fibroblasts and attenuated dermal thickening and collagen deposition in bleomycin\u2010treated mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2013mtDNA\u2013cGAS\u2013STING axis drives fibroblast activation and skin fibrosis in SSc, representing a promising therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70261","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T12:46:42Z","timestamp":1782218802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fibroblast Mitochondrial Ca\n                    <sup>2+<\/sup>\n                    Overload Drives Skin Fibrosis via Mitochondrial\n                    <scp>DNA<\/scp>\n                    Leakage and Cyclic\n                    <scp>GMP<\/scp>\n                    \u2010\n                    <scp>AMP<\/scp>\n                    Synthase\u2013Stimulator of Interferon Genes Activation in Systemic Sclerosis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-6862","authenticated-orcid":false,"given":"Xiaoyun","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Huashan Hospital Fudan University  Shanghai China"},{"name":"Institute of Rheumatology, Immunology, and Allergy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Huashan Hospital Fudan University  Shanghai China"},{"name":"Institute of 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Rheumatology, Immunology, and Allergy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Cao","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Huashan Hospital Fudan University  Shanghai China"},{"name":"Institute of Rheumatology, Immunology, and Allergy Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxia","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology The Affiliated Hospital of Inner Mongolia Medical University  Hohhot City China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Central Lab, 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