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Here, we uncover a previously unrecognized role of NOP2\/Sun RNA methyltransferase 2 (NSUN2), an RNA 5\u2010methylcytosine (m\n                    <jats:sup>5<\/jats:sup>\n                    C) methyltransferase, in safeguarding pregnancy by remodeling trophoblast mediated macrophage function. We demonstrate that NSUN2 expression and global m\n                    <jats:sup>5<\/jats:sup>\n                    C modification levels are significantly diminished in villous tissues from URSA patients. Trophoblast\u2010specific ablation of\n                    <jats:italic>Nsun2<\/jats:italic>\n                    in mice resulted in embryonic absorption and decreased placental and fetal weight in mice underscoring its functional necessity in pregnancy maintenance. Mechanistically, loss of\n                    <jats:italic>NSUN2<\/jats:italic>\n                    in trophoblasts impairs m\n                    <jats:sup>5<\/jats:sup>\n                    C deposition on\n                    <jats:italic>TGFB1<\/jats:italic>\n                    mRNA, reducing the recruitment of the m\n                    <jats:sup>5<\/jats:sup>\n                    C reader YBX1, which in turn destabilizes the transcript and diminishes TGF\u2010\u03b21 secretion, thereby suppressing M2 macrophage polarization and skewing the balance toward a pro\u2010inflammatory M1 phenotype. Notably, restoration of NSUN2 via adenovirus\u2010mediated gene delivery effectively rescues TGF\u2010\u03b21 expression, rectifies macrophage imbalance, and alleviates embryo resorption in URSA mouse models. Collectively, our findings establish NSUN2 as an essential epigenetic regulator governing maternal\u2010fetal immune tolerance through m\n                    <jats:sup>5<\/jats:sup>\n                    C\u2010dependent stabilization of\n                    <jats:italic>TGFB1<\/jats:italic>\n                    mRNA, and identify the NSUN2 \/YBX1\/TGFB1 axis as a potential diagnostic biomarker and therapeutic target for URSA.\n                  <\/jats:p>","DOI":"10.1002\/advs.77562","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:35:27Z","timestamp":1789364127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NSUN2\u2010Mediated m\n                    <sup>5<\/sup>\n                    C Modification of\n                    <i>TGFB1<\/i>\n                    in Trophoblasts Remodels Macrophage Function to Prevent 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