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Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Despite the rapid development of immunosuppressive drugs, acute rejection (AR) remains a cause of allograft dysfunction and allograft failure. Although endometrial regenerative cell-derived exosomes (ERC-Exos) effectively alleviate AR, more research is required to fully understand the underlying mechanisms. Thus, this study aimed to determine whether sirtuin 6 (SIRT6) mediates the therapeutic effect of ERC-Exos on AR and elucidate the underlying mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression of SIRT6 was verified in ERC-Exos by Western blot. ERC-Exos with extremely low expression of SIRT6 (SIRT6-KD-ERC-Exos) were obtained by transducing shRNA-SIRT6 in ERCs. C57BL\/6 recipient mice were transplanted with heart grafts from BALB\/c donor mice and divided into three groups: untreated, ERC-Exo-treated, and SIRT6-KD-ERC-Exo-treated groups. Recipient mice were sacrificed on post-operative day 8 for the determination of graft pathological changes, intra-graft immunocyte infiltration, splenic CD4<jats:sup>+<\/jats:sup> T cell populations, and serum cytokine levels <jats:italic>in vivo<\/jats:italic>. The proportion of CD4<jats:sup>+<\/jats:sup> T cells and their secreting cytokine levels were determined <jats:italic>in vitro<\/jats:italic>. Besides, the underlying mechanisms were also investigated <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ERC-Exos expressed SIRT6, and cardiac graft survival was increased by SIRT6-expressing ERC-Exos. Graft pathological damage, intra-graft CD4<jats:sup>+<\/jats:sup> T cell infiltration, and intra-graft inflammatory (Th1 and Th17) cell infiltration decreased, and intra-graft and serum inflammatory cytokine (interferon (IFN)-\u03b3 and interleukin (IL)-17) levels decreased in the SIRT6-expressing ERC-Exo-treated mice. Furthermore, in the recipient mice, ERC-Exo treatment markedly increased the differentiation of regulatory T cells (Tregs) while significantly decreasing that of Th1 and Th17 cells. In a similar vein, ERC-Exo therapy raised the levels of the anti-inflammatory cytokine IL-10 <jats:italic>in vitro<\/jats:italic> while decreasing those of IFN-\u03b3 and IL-17. By suppressing the expression of important proteins linked to glutaminolysis and further deactivating the mammalian target of rapamycin complex 1 (mTORC1) pathway, ERC-Exos reduced the uptake and use of glutamine in na\u00efve CD4<jats:sup>+<\/jats:sup> T cells, according to mechanism exploration. In contrast, SIRT6-KD-ERC-Exos considerably reversed these trends and changes both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>SIRT6 is crucial in mediating ERC-Exos to remodel CD4<jats:sup>+<\/jats:sup> T cell differentiation by weakening c-Myc-dependent glutaminolysis, thereby alleviating AR.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1564382","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T05:32:51Z","timestamp":1758173571000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Sirtuin 6 mediates the therapeutic effect of endometrial regenerative cell-derived exosomes in alleviation of acute transplant rejection by weakening c-myc-dependent glutaminolysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Tong","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenglu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Shao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yini","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiyi","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongda","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangmei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1111\/j.1365-2249.2007.03356.x","article-title":"The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease","volume":"148","author":"Afzali","year":"2007","journal-title":"Clin. 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