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Here, we identify a post-transcriptional regulatory axis linking the RNA-binding protein Musashi-1 (MSI1) to iron dependent DNA demethylation via the ferritin like gene\n                    <jats:italic>Fthl17c<\/jats:italic>\n                    . Genetic ablation of MSI1 and its short isoform MSI1-C in mESCs induced spontaneous differentiation and was accompanied by downregulation of\n                    <jats:italic>Fthl17<\/jats:italic>\n                    family genes. Among these,\n                    <jats:italic>Fthl17c<\/jats:italic>\n                    was directly bound and stabilized by MSI1, and its depletion reduced intracellular ferrous iron (Fe\n                    <jats:sup>2<\/jats:sup>\n                    \u207a), impaired ten eleven translocation (TET) enzyme activity, and increased global 5-methylcytosine (5mC) levels. Restoration of\n                    <jats:italic>Fthl17c<\/jats:italic>\n                    expression rescued TET activity, reduced DNA methylation, and reinstated pluripotency associated gene expression, whereas extracellular Fe\n                    <jats:sup>2<\/jats:sup>\n                    \u207a supplementation alone was insufficient. In contrast, vitamin C, which preserves redox active Fe\n                    <jats:sup>2<\/jats:sup>\n                    \u207a, effectively restored DNA demethylation, highlighting the requirement for bioavailable iron in TET mediated epigenetic regulation. Biochemical and imaging analyses further revealed that FTHL17C interacts with TET1 in the nucleus, supporting a role in facilitating iron dependent catalysis. Together, these findings define an MSI1-FTHL17C-Fe\n                    <jats:sup>2<\/jats:sup>\n                    \u207a-TET axis that integrates post transcriptional control of iron homeostasis with epigenetic remodeling to preserve the pluripotent and plastic state of embryonic stem cells.\n                  <\/jats:p>","DOI":"10.1186\/s13619-026-00288-8","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:17:58Z","timestamp":1778037478000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MSI1-FTHL17C-iron circuit couples metabolic and epigenetic control of pluripotency in mouse embryonic stem cells"],"prefix":"10.1186","volume":"15","author":[{"given":"Qianyan","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiazhen","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liming","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8097-7222","authenticated-orcid":false,"given":"Gufa","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3298-8143","authenticated-orcid":false,"given":"Youwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"288_CR1","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.stem.2018.05.020","volume":"23","author":"K Adachi","year":"2018","unstructured":"Adachi K, Kopp W, Wu G, Heising S, Greber B, Stehling M, et al. 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Gufa Lin is a member of the Editorial Board for Cell Regeneration and a leading editor of collection \u201cThe Lineage and Plasticity of Adult Stem\/Progenitor Cells\u201d. He\u00a0was not involved in the journal\u2019s review of or decisions related to this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14"}}