{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T01:49:13Z","timestamp":1775353753951,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Treatment with human umbilical cord mesenchymal stem cells (hUC\u2010MSCs) attenuated the clinical manifestations of systemic lupus erythematosus (SLE). We investigated the metabolic mechanism whereby hUC\u2010MSCs modify CD4<jats:sup>+<\/jats:sup> T cell cytokine secretion in lupus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study enrolled 30 untreated lupus patients and 20 sex, age, and body mass index matched healthy controls (HCs). CD4<jats:sup>+<\/jats:sup> T cells were isolated by magnetic sorting, and stimulated with anti\u2010CD3\/CD28. The hUC\u2010MSCs treatment (MSCT) groups were coculturing hUC\u2010MSCs to CD4<jats:sup>+<\/jats:sup> T cells from moderate and severe SLE (SLE\u2010MS) groups for 72\u2009h at ratios of 1:25 (T1), 1:10 (T2), and 1:5 (T3). Cytokine concentration and proliferation of the CD4<jats:sup>+<\/jats:sup> T cells were measured by Luminex liquid chip assay and cell counting kit\u20108, respectively. Glucose metabolic capacity was measured by Seahorse real\u2010time metabolic analysis. The role of hUC\u2010MSCs on cytokine secretion was analyzed by transcriptome sequencing. Glucose enzymes levels and HSP90AA1\/PI3K\/AKT pathway activity were analyzed by real\u2010time quantitative PCR and western blot. The CD4<jats:sup>+<\/jats:sup> T cell subsets were detected by flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with HCs, the enhanced glycolysis and mitochondrial oxygen consumption of SLE\u2010CD4<jats:sup>+<\/jats:sup> T cells were positively associated with disease activity. Treatment with hUC\u2010MSCs proportionally decreased glucose metabolism and proliferation of SLE\u2010CD4<jats:sup>+<\/jats:sup> T cells. The hUC\u2010MSCs treatment significantly diminished supernatant concentrations of interferon\u2010\u03b3, tumor necrosis factor\u2010\u03b1, interleukin (IL)\u20104, and IL\u201017 in SLE\u2010MS group, as well as inhibited HSP90AA1 in the glucose\u2010activated PI3K\u2010AKT pathway. In animal experiment, the systemic administration of hUC\u2010MSCs and inhibition of HSP90AA1 resulted in a reduction of glucose metabolites, enzymes, pro\u2010inflammatory factor levels, and HSP90AA1<jats:italic>\/<\/jats:italic>PI3K\/AKT signaling pathway activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The hUC\u2010MSCs treatment inhibited overactive glucose metabolism of SLE\u2010CD4<jats:sup>+<\/jats:sup> T cells. HSP90AA1 in the PI3K\u2010AKT pathway induced by the glucose metabolism may be involved in the anti\u2010inflammatory function of hUC\u2010MSCs treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/iid3.70239","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T11:34:49Z","timestamp":1755084889000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human Umbilical Cord Mesenchymal Stem Cells Modulate Cytokine Secretion of CD4<sup>+<\/sup> T Cell in Systemic Lupus Erythematosus by Inhibiting HSP90AA1 in the Glucose\u2010Activated PI3K\u2010AKT Pathway"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3282-233X","authenticated-orcid":false,"given":"Lu","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology The Second Hospital of Hebei Medical University Shijiazhuang Hebei China"},{"name":"Hebei International 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