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Therefore, there is an urgent need to develop novel treatment strategies with improved tissue targeting and safety profiles. In this study, a refrigerated\u2010treated mesenchymal stem cell (RT\u2010MSCs) system was established by culturing human umbilical cord\u2010derived MSCs under controlled low\u2010temperature conditions. The antifibrotic effects of RT\u2010MSCs were evaluated through both in vivo and in vitro experiments, together with an assessment of their regulatory role in mitochondrial autophagy. Their lesion\u2010targeting capacity was also investigated. Furthermore, the effects of RT\u2010MSCs on gut microbiota composition and metabolic pathways in model mice were comprehensively analyzed using 16S rRNA sequencing and intestinal content metabolomics, and the safety of RT\u2010MSCs was systematically evaluated. The results demonstrated that RT\u2010MSCs effectively attenuated fibrosis progression by modulating mitochondrial autophagy. Within 30\u00a0min after administration, RT\u2010MSCs accumulated at lesion sites and persisted for up to 7 days. RT\u2010MSCs significantly improved intestinal microbiota dysbiosis in scleroderma mice and regulated the expression of associated intestinal metabolites. In summary, as an optimized stem cell\u2010based therapeutic strategy, RT\u2010MSCs offer new insights and potential avenues for treating scleroderma.<\/jats:p>","DOI":"10.1002\/advs.202515505","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T19:26:26Z","timestamp":1774985186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Time\u2010Controlled Refrigerated Stem Cell Therapy Mitigates Scleroderma Fibrosis via Modulation of Mitochondrial Autophagy and Gut Metabolism"],"prefix":"10.1002","volume":"13","author":[{"given":"Xue","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology China\u2010Japan Union Hospital, Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenfei","family":"Kong","sequence":"additional","affiliation":[{"name":"Scientific Research Center China\u2010Japan Union 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