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Nicotinamide phosphoribosyltransferase (NAMPT), the rate\u2010limiting enzyme of the NAD\n                    <jats:sup>+<\/jats:sup>\n                    salvage pathway, converts nicotinamide (NAM) to NAD\n                    <jats:sup>+<\/jats:sup>\n                    precursor nicotinamide mononucleotide (NMN). Although restriction of NAD\n                    <jats:sup>+<\/jats:sup>\n                    metabolism has been implicated in leading to fetal loss in pregnant mice, whether NAMPT is involved in regulating maternal\u2010fetal maintenance and the underlying mechanism has been poorly understood. Here, we demonstrated that primary decidual macrophages from RSA patients showed decreased expression of NAMPT and impaired NAD\n                    <jats:sup>+<\/jats:sup>\n                    metabolism.\n                    <jats:italic>Nampt<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice exhibited a significant elevation in the embryonic absorption rate compared with that of wild\u2010type (WT) mice, and adoptive transferring WT macrophages into\n                    <jats:italic>Nampt<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice significantly ameliorated the adverse pregnancy outcome. Genetic and pharmacological interference of NAMPT disrupted the differentiation of M1 macrophages. Mechanically, deficiency of NAMPT inhibited gasdermin D (GSDMD) cleavage independently from canonical pyroptosis. The cleaved N\u2010terminal fragment of GSDMD functioned as a stimulus to activate the NF\u2010\u03baB pathway and subsequently promoted TNF\u2010\u03b1 transcription by phospho\u2010P65 (S536). NMN replenishment ameliorated the dysregulation of M1 macrophage differentiation, the infiltration of trophoblasts, and fetal loss. Our study reveals an NAMPT\u2010associated immunopathogenesis of early pregnancy loss and provides a new idea for the therapeutic strategy for RSA patients.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500462r","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T07:27:56Z","timestamp":1749626876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>NAD<\/scp>\n                    <sup>+<\/sup>\n                    Metabolism Maintains the Homeostasis of Decidual Macrophages in Early Pregnancy"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5919-7926","authenticated-orcid":false,"given":"Yongbo","family":"Zhao","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Lu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyi","family":"Cai","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal\u2010Fetal Medicine and Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Jin","sequence":"additional","affiliation":[{"name":"Hospital of Obstetrics and Gynecology Fudan University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.082800et"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-100003"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60561"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj2488"},{"key":"e_1_2_9_6_1","article-title":"Modulators of the Balance Between M1 and M2 Macrophages During Pregnancy","volume":"8","author":"Zhang Y. 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