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However, poor graft survival and immune rejection remain major obstacles to clinical application. Our previous work established that METTL3 overexpression enhances IPCs induction efficiency and maturation, yet whether it improves in\u00a0vivo transplantation efficacy and the associated mechanisms remain unexplored. WT\u2010IPCs and Mettl3\u2010OE\u2010IPCs were transplanted beneath the renal capsule of streptozotocin\u2010induced type 1 diabetic mice. Blood glucose, serum C\u2010peptide, in\u00a0vivo GFP fluorescence imaging, and histology were used to assess graft survival. Untargeted metabolomics of intestinal contents identified differential metabolites. Western blot, RT\u2010qPCR, immunofluorescence, and ELISA examined associations among METTL3, IDO1, and kynurenine (Kyn) in\u00a0vitro. A four\u2010group rescue experiment (WT\u2010IPCs, WT\u2010IPCs+Kyn, Mettl3\u2010OE\u2010IPCs, Mettl3\u2010OE\u2010IPCs+1\u2010MT) evaluated the causal contribution of Kyn. Immunofluorescence and immunohistochemistry assessed endogenous islet apoptosis and local immune infiltration. Mettl3\u2010OE\u2010IPCs transplantation significantly improved glycemic control and prolonged graft survival compared with the WT\u2010IPCs group. Endogenous islets in the Mettl3\u2010OE\u2010IPCs group showed elevated insulin expression, reduced BAX, and increased Bcl\u20102. Serum C\u2010peptide levels were also higher in this group. Untargeted metabolomics identified Kyn as the significantly enriched metabolite in the intestinal contents of the Mettl3\u2010OE\u2010IPCs group. Serum Kyn levels were markedly elevated (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). In\u00a0vitro, METTL3 overexpression was associated with IDO1 upregulation at mRNA and protein levels and increased Kyn secretion. Rescue experiments showed that Kyn supplementation conferred comparable glycemic benefits and islet apoptosis suppression to the Mettl3\u2010OE\u2010IPCs group; IDO1 inhibition with 1\u2010MT substantially attenuated these advantages (IPGTT AUC,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Immune profiling revealed splenic CD25\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell expansion and reduced transplant side renal CD8+ T cell infiltration in Kyn\u2010treated and the Mettl3\u2010OE\u2010IPCs group; both effects were abrogated by 1\u2010MT. This study shows that METTL3 overexpression is associated with IDO1 upregulation and elevated systemic Kyn levels. These changes are accompanied by improved graft survival and reduced endogenous islet apoptosis. Rescue experiments show that Kyn is both sufficient and necessary for these effects. These findings suggest that the METTL3\u2010IDO1\u2010Kyn pathway may be a potential target for improving cell replacement therapy for diabetes.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602555r","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:27:45Z","timestamp":1783351665000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["METTL3\u2010Activated IDO1\u2010Kynurenine Pathway in Insulin\u2010Producing Cells Enhances Graft Survival and Attenuates Endogenous Islet Apoptosis in Diabetic Mice"],"prefix":"10.1096","volume":"40","author":[{"given":"Shan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Institute for the Study of Endocrinology and Metabolism in Jiangxi Province  Nanchang Jiangxi 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Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Institute for the Study of Endocrinology and Metabolism in Jiangxi Province  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Institute for the Study of Endocrinology and Metabolism in Jiangxi Province  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0138-6845","authenticated-orcid":false,"given":"Jianping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism of the Second Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Institute for the Study of Endocrinology and 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