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While na\u00efve human PSCs (hPSCs) harbor an unstable genome limiting their broad applications, mouse embryonic stem cells (mESCs) uniquely exhibit both robust pluripotency and high genomic stability. Understanding whether and how these two attributes are co-regulated in mESCs could provide critical insights for producing safe and authentic hPSCs. Here, we reveal that the coordination of na\u00efve pluripotency and genomic stability in mESCs is governed by a novel core pluripotency regulator, ZFP998. ZFP998 binds to promoters and enhancers of key ESC-identity genes, as well as to numerous DNA damage response and repair genes, thereby regulating their expression. Depletion of Zfp998 leads to the loss of na\u00efve pluripotency and induces severe genomic instability. Conversely, overexpression of ZFP998 is sufficient to reprogram epiblast stem cells back to a na\u00efve pluripotent state. Importantly, ectopic expression of ZFP998 in hESCs enhances both pluripotency and genomic stability. These findings suggest that this coupled regulatory mechanism is conserved in humans and provide a promising new strategy for generating safe, na\u00efve hPSCs.<\/jats:p>","DOI":"10.1093\/nar\/gkag546","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T11:22:02Z","timestamp":1779103322000},"source":"Crossref","is-referenced-by-count":0,"title":["Na\u00efve pluripotency and genomic stability are coordinated in embryonic stem cells by a novel pluripotency regulator ZFP998"],"prefix":"10.1093","volume":"54","author":[{"given":"Min","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming 650201 ,","place":["China"]},{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming, Yunnan 650201 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming 650201 ,","place":["China"]},{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming, Yunnan 650201 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-wen","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , Beijing 101408 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-huan","family":"Zhong","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , Beijing 101408 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Kunming 650201 ,","place":["China"]},{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming, Yunnan 650201 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7006-4737","authenticated-orcid":false,"given":"Hu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 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