{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T23:01:48Z","timestamp":1784502108760,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2025M782226 to Z.L."],"award-info":[{"award-number":["2025M782226 to Z.L."]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["GZB20250512 to Z.L."],"award-info":[{"award-number":["GZB20250512 to Z.L."]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The transition between naive and primed pluripotency is governed by dynamic signaling networks and transcriptional circuits. While the janus kinase (JAK)\/signal transducer and activator of transcription 3 (STAT3) pathway is the master driver of naive pluripotency, the intrinsic negative feedback mechanisms that restrict its activation in primed epiblast stem cells (EpiSCs) remain incompletely defined. This study aimed to characterize the functional role of Suppressor of Cytokine Signaling 3 (SOCS3) in the primed-to-naive pluripotency transition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)\/Cas9 (CRISPR-associated protein 9) -mediated\n                      <jats:italic>Socs3<\/jats:italic>\n                      knockout (KO) was generated in mouse EpiSCs, followed by primed-to-naive reprogramming induction in 2i\/LIF [LIF (leukemia inhibitory factor), PD0325901 and CHIR99021) culture system. Molecular and phenotypic changes were evaluated via quantative real time PCR (qRT-PCR), Western blot, flow cytometry and immunofluorescence. Multilineage differentiation as-says were performed to verify pluripotency, and the STAT3-specific inhibitor Stattic was used to confirm the pathway dependence of the reprogramming phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Socs3<\/jats:italic>\n                      was highly expressed in naive embryonic stem cells (ESCs) but minimally detected in EpiSCs.\n                      <jats:italic>Socs3<\/jats:italic>\n                      deletion uncoupled the JAK\/STAT3 negative feedback loop, causing sustained STAT3 Tyr705 phosphorylation that drove rapid and successful primed-to-naive conversion. The resulting reprogrammed naive ESCs (rnESCs) reactivated the core naive transcriptional network and acquired multilineage differentiation potential.\n                      <jats:italic>Socs3<\/jats:italic>\n                      deficiency also delayed exit from naive pluripotency, and Stattic treatment completely abrogated\n                      <jats:italic>Socs3<\/jats:italic>\n                      KO-mediated reprogramming.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SOCS3 acts as a pivotal inducible barrier to the primed-to-naive pluripotency transition. Eliminating SOCS3-mediated negative regulation to sustain STAT3 activation is an effective strategy to overcome stem cell reprogramming barriers, providing a key target for the precise manipulation of pluripotent stem cell (PSC) fate.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1857225","type":"journal-article","created":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T22:10:15Z","timestamp":1784499015000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SOCS3 deficiency drives the primed to naive pluripotency transition by sustaining STAT3 activation"],"prefix":"10.3389","volume":"17","author":[{"given":"Renhong","family":"Lu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suoni","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Du","sequence":"additional","affiliation":[{"name":"Jinzhou Medical University","place":["Jinzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Jinzhou Medical University","place":["Jinzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheyi","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1559183","DOI":"10.3389\/fcell.2025.1559183","article-title":"Epigenetic regulation of reprogramming and pluripotency: insights from histone modifications and their implications for cancer stem cell therapies","volume":"13","author":"Bae","year":"2025","journal-title":"Front. Cell Dev. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/s41588-020-00770-2","article-title":"Metabolic control of DNA methylation in naive pluripotent cells","volume":"53","author":"Betto","year":"2021","journal-title":"Nat. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"113612","DOI":"10.1016\/j.celrep.2023.113612","article-title":"Dynamic IL-6R\/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells","volume":"43","author":"Blaszczak","year":"2024","journal-title":"Cell Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"111712","DOI":"10.1016\/j.yexcr.2019.111712","article-title":"GP130 signaling and the control of na\u00efve pluripotency in humans, monkeys, and pigs","volume":"386","author":"Bourillot","year":"2020","journal-title":"Exp. Cell Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.cellsig.2008.11.002","article-title":"Deletion of the SOCS box of suppressor of cytokine signaling 3 (SOCS3) in embryonic stem cells reveals SOCS box-dependent regulation of JAK but not STAT phosphorylation","volume":"21","author":"Boyle","year":"2009","journal-title":"Cell Signal"},{"key":"B6","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/s41556-023-01131-x","article-title":"Esrrb guides naive pluripotent cells through the formative transcriptional programme","volume":"25","author":"Carbognin","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"eadq7469","DOI":"10.1126\/sciadv.adq7469","article-title":"Developmental regulation of Erk signaling by mitotic kinases","volume":"12","author":"Chen","year":"2026","journal-title":"Sci. Adv."},{"key":"B8","doi-asserted-by":"publisher","first-page":"eabk0013","DOI":"10.1126\/sciadv.abk0013","article-title":"Genome-wide screening identifies Polycomb repressive complex 1.3 as an essential regulator of human na\u00efve pluripotent cell reprogramming","volume":"8","author":"Collier","year":"2022","journal-title":"Sci. Adv."},{"key":"B9","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1126\/science.1231143","article-title":"Multiplex genome engineering using CRISPR\/Cas systems","volume":"339","author":"Cong","year":"2013","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.stem.2024.01.009","article-title":"Hallmarks of totipotent and pluripotent stem cell states","volume":"31","author":"DU","year":"2024","journal-title":"Cell Stem Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/s41467-022-35775-4","article-title":"Molecular versatility during pluripotency progression","volume":"14","author":"Furlan","year":"2023","journal-title":"Nat. Commun."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.3390\/cells11152289","article-title":"A genome-wide CRISPR screen identifies factors regulating pluripotency exit in Mouse embryonic stem cells","volume":"11","author":"Gao","year":"2022","journal-title":"Cells"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1242\/dev.030957","article-title":"Klf4 reverts developmentally programmed restriction of ground state pluripotency","volume":"136","author":"Guo","year":"2009","journal-title":"Development"},{"key":"B14","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/s41420-022-00922-9","article-title":"Inhibition of STAT3(Y705) phosphorylation by Stattic suppresses proliferation and induces mitochondrial-dependent apoptosis in pancreatic cancer cells","volume":"8","author":"Guo","year":"2022","journal-title":"Cell Death Discov."},{"key":"B15","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41467-024-44969-x","article-title":"Self-renewing human na\u00efve pluripotent stem cells dedifferentiate in 3D culture and form blastoids spontaneously","volume":"15","author":"Guo","year":"2024","journal-title":"Nat. Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.biomaterials.2017.12.014","article-title":"VE-Cadherin regulates the self-renewal of mouse embryonic stem cells via LIF\/Stat3 signaling pathway","volume":"158","author":"He","year":"2018","journal-title":"Biomaterials"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1612868","DOI":"10.3389\/fgeed.2025.1612868","article-title":"Stem cell and CRISPR\/Cas9 gene editing technology in Alzheimer's disease therapy: from basic research to clinical innovation","volume":"7","author":"He","year":"2025","journal-title":"Front. Genome"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1002\/stem.1609","article-title":"STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates","volume":"32","author":"Huang","year":"2014","journal-title":"Stem Cells"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1494398","DOI":"10.3389\/fcell.2024.1494398","article-title":"Advances in understanding the regulation of pluripotency fate transition in embryonic stem cells","volume":"12","author":"Jia","year":"2024","journal-title":"Front. Cell Dev. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.stem.2021.11.002","article-title":"Capture of mouse and human stem cells with features of formative pluripotency","volume":"28","author":"Kinoshita","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"102783","DOI":"10.1016\/j.isci.2021.102783","article-title":"AMPK activation reverts mouse epiblast stem cells to naive state","volume":"24","author":"Liu","year":"2021","journal-title":"iScience"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2576","DOI":"10.1007\/s12015-023-10585-3","article-title":"Recent advances in CRISPR\/Cas9 delivery approaches for therapeutic gene editing of stem cells","volume":"19","author":"Lotfi","year":"2023","journal-title":"Stem Cell Rev. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.jare.2024.11.037","article-title":"Hypo-osmolarity promotes naive pluripotency by reshaping cytoskeleton and increasing chromatin accessibility","volume":"75","author":"Lu","year":"2025","journal-title":"J. Adv. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"108140","DOI":"10.1016\/j.jbc.2024.108140","article-title":"Interplay of chromatin remodeling BAF complexes in mouse embryonic and epiblast stem cell conversion and maintenance","volume":"301","author":"Ma","year":"2025","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1038\/s41556-025-01767-x","article-title":"Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells","volume":"27","author":"Mccreery","year":"2025","journal-title":"Nat. Cell Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"dev199950","DOI":"10.1242\/dev.199950","article-title":"Cell state transitions: definitions and challenges","volume":"148","author":"Mulas","year":"2021","journal-title":"Development"},{"key":"B27","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.stem.2009.05.015","article-title":"Naive and primed pluripotent states","volume":"4","author":"Nichols","year":"2009","journal-title":"Cell Stem Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e2303395","DOI":"10.1002\/advs.202303395","article-title":"Cyclic stretch promotes cellular reprogramming process through cytoskeletal-nuclear mechano-coupling and epigenetic modification","volume":"10","author":"Park","year":"2023","journal-title":"Adv. Sci. (Weinh)"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1016\/j.stem.2021.10.001","article-title":"The exploration of pluripotency space: charting cell state transitions in peri-implantation development","volume":"28","author":"Pera","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e70152","DOI":"10.1002\/mco2.70152","article-title":"STAT3 signaling pathway in health and disease","volume":"6","author":"Samad","year":"2020","journal-title":"MedComm"},{"key":"B31","doi-asserted-by":"publisher","first-page":"7879","DOI":"10.1038\/s41467-024-51794-9","article-title":"FoxO transcription factors actuate the formative pluripotency specific gene expression programme","volume":"15","author":"Santini","year":"2024","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1242\/dev.142679","article-title":"Formative pluripotency: the executive phase in a developmental continuum","volume":"144","author":"Smith","year":"2017","journal-title":"Development"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2008890118","DOI":"10.1073\/pnas.2008890118","article-title":"OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms","volume":"118","author":"Stirparo","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.cub.2013.12.040","article-title":"NANOG amplifies STAT3 activation and they synergistically induce the naive pluripotent program","volume":"24","author":"Stuart","year":"2014","journal-title":"Curr. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.stem.2019.07.009","article-title":"Distinct molecular trajectories converge to induce naive pluripotency","volume":"25","author":"Stuart","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nrm.2016.8","article-title":"A decade of transcription factor-mediated reprogramming to pluripotency","volume":"17","author":"Takahashi","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"707","DOI":"10.3390\/cells13080707","article-title":"Lineage reprogramming: genetic, chemical, and physical cues for cell fate conversion with a focus on neuronal direct reprogramming and pluripotency reprogramming","volume":"13","author":"Umeyama","year":"2024","journal-title":"Cells"},{"key":"B38","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/s41419-019-1417-4","article-title":"m(6)A methylation controls pluripotency of porcine induced pluripotent stem cells by targeting SOCS3\/JAK2\/STAT3 pathway in a YTHDF1\/YTHDF2-orchestrated manner","volume":"10","author":"Wu","year":"2019","journal-title":"Cell Death Dis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.stem.2010.06.022","article-title":"Stat3 activation is limiting for reprogramming to ground state pluripotency","volume":"7","author":"Yang","year":"2010","journal-title":"Cell Stem Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.stemcr.2019.02.010","article-title":"Genome-Scale CRISPRa screen identifies novel factors for cellular reprogramming","volume":"12","author":"Yang","year":"2019","journal-title":"Stem Cell Rep."},{"key":"B41","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nbt780","article-title":"Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture","volume":"21","author":"Ying","year":"2003","journal-title":"Nat. Biotechnol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/s41556-020-0516-x","article-title":"BMP4 resets mouse epiblast stem cells to naive pluripotency through ZBTB7A\/B-mediated chromatin remodelling","volume":"22","author":"Yu","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.stem.2020.11.003","article-title":"Derivation of intermediate pluripotent stem cells amenable to primordial germ cell specification","volume":"28","author":"Yu","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2168","DOI":"10.3390\/biomedicines11082168","article-title":"Progress and prospects of gene editing in pluripotent stem cells","volume":"11","author":"Zhang","year":"2023","journal-title":"Biomedicines"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e2416478","DOI":"10.1002\/advs.202416478","article-title":"Cardiomyocyte-Enriched USP20 ameliorates pathological cardiac hypertrophy by targeting STAT3 deubiquitination","volume":"12","author":"Zhong","year":"2025","journal-title":"Adv. Sci. (Weinh)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13287-024-03831-z","article-title":"Genome-scale CRISPR-Cas9 screening in stem cells: theories, applications and challenges","volume":"15","author":"Zhou","year":"2024","journal-title":"Stem Cell Res. Ther."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1857225\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T22:10:17Z","timestamp":1784499017000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1857225\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":46,"alternative-id":["10.3389\/fgene.2026.1857225"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1857225","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]},"article-number":"1857225"}}