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This study identifies a pivotal role for Nicotinamide adenine dinucleotide (NAD\n                    <jats:sup>+<\/jats:sup>\n                    ) metabolism in regulating ZGA through poly(ADP\u2011ribose) polymerase 7(PARP7)\u2010mediated ADP\u2010ribosylation. Using ultra\u2010low input embryo metabolomics, we profiled metabolism from zygote to blastocyst, revealing a significant NAD\n                    <jats:sup>+<\/jats:sup>\n                    decline at the 2\u2010cell stage. This shift coincided with specific upregulation of the mono\u2010ADP\u2010ribosyltransferase PARP7, confirmed by transcriptomics, quantitative RT\u2010PCR, western blot, and immunofluorescence. Genetic knockdown via trim\u2010away technology or pharmacological inhibition with RBN\u20102397 caused developmental delay\/arrest at the 2\u2010cell stage, impaired blastocyst formation, and defective ZGA. Mechanistically, PARP7 deficiency reduced chromatin accessibility (ATAC\u2010seq), diminished H3K4ac and H3K27ac marks, and impaired RNA polymerase II transcription. Integrated proteomics and ADP\u2010ribosylome analysis of late 2\u2010cell embryos identified UHRF1 as a key PARP7 target, mono\u2010ADP\u2010ribosylated at lysines K30 and K31. This modification stabilized UHRF1 protein (cycloheximide chase), and UHRF1 overexpression partially rescued the transcriptional defects associated with ZGA from PARP7 inhibition. Our findings establish a metabolic\u2010epigenetic axis wherein NAD\n                    <jats:sup>+<\/jats:sup>\n                    metabolism, via PARP7\u2010mediated ADP\u2010ribosylation of UHRF1, regulates chromatin remodeling and transcriptional activation during ZGA, offering fundamental insights into early development.\n                  <\/jats:p>","DOI":"10.1002\/advs.76136","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:08:46Z","timestamp":1781525326000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NAD\n                    <sup>+<\/sup>\n                    Metabolism Licenses Zygotic Genome Activation via PARP7\u2010Mediated ADP\u2010Ribosylation of UHRF1 in Mouse Early Embryos"],"prefix":"10.1002","volume":"13","author":[{"given":"Guangyi","family":"Cao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"},{"name":"Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"},{"name":"Center for Reproductive Medicine and Obstetrics and Gynecology Joint Institute of Nanjing Drum Tower Hospital for Life and Health College of Life Science Nanjing Normal University  Nanjing China"},{"name":"Jiangsu Human Reproductive Function Remodeling Engineering Research Center  Nanjing China"},{"name":"Nanjing Clinical Medical Center for Reproductive Medicine  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Chen","sequence":"additional","affiliation":[{"name":"The Research Institute of Advanced Technologies Ningbo University  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4470-2073","authenticated-orcid":false,"given":"Yanbo","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixin","family":"Shi","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine and Obstetrics and Gynecology Joint Institute of Nanjing Drum Tower Hospital for Life and Health College of Life Science Nanjing Normal University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aolei","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Mao","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine and Obstetrics and Gynecology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganggui","family":"Lou","sequence":"additional","affiliation":[{"name":"China Innovation Instrument Company Ltd.  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