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While mesenchymal stem cells (MSCs) hold therapeutic promise, their efficacy varies substantially, likely due to their plasticity and capacity to adopt pro-inflammatory (MSC1) or anti-inflammatory (MSC2) functional states in response to different microenvironments. Here, we report for the first time that IL-27, via JAK1\u2013STAT1 signaling, up-regulates indoleamine 2,3-dioxygenase (IDO) in MSCs, driving MSC differentiation toward an IDO-positive MSC2 phenotype with low immunogenicity. These IDO-positive MSC2 cells produce kynurenine and kynurenic acid, the metabolites of tryptophan, which bind to the intracellular aryl hydrocarbon receptor. This interaction stimulates an increase in the anti-inflammatory factor TSG-6 and induces the differentiation of regulatory T cells. Notably, IL-27-conditioned MSC2 demonstrated superior therapeutic efficacy compared to conventional MSCs in a murine lupus nephritis model. In conclusion, this study revealed that IL-27 is a critical modulator of MSC immune plasticity and presented a novel therapeutic strategy utilizing IL-27-enhanced MSC2 for autoimmune diseases.<\/jats:p>","DOI":"10.34133\/research.0748","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T13:10:21Z","timestamp":1748610621000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":11,"title":["IL-27 Modulates Mesenchymal Stem Cell Immunoplasticity for Enhanced Lupus Nephritis Therapy via the JAK1\u2013STAT1\u2013IDO Axis and Tryptophan Metabolic Orchestration"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6302-5235","authenticated-orcid":false,"given":"Cheng","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Nephrology, \rChina-Japan Friendship Hospital, Beijing 100029, 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(Zyyzdxk..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (Zyyzdxk..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meihan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (Zyyzdxk..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenge","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, \rChina-Japan Friendship Hospital, Beijing 100029, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (Zyyzdxk..."},{"name":"Department of Nephrology and Institute of Kidney Diseases, West China Hospital, \rSichuan University, Chengdu 610041, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Yuan","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-Vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (Zyyzdxk..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"issue":"17","key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1001\/jama.2024.2315","article-title":"Systemic lupus erythematosus: A review","volume":"331","author":"Siegel 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