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We investigated whether EZH2\u2010mediated H3K27me3 deposition represses thyroid differentiation genes (TDGs) in ATC cells. Online ChIP\u2010seq analyses and CUT&amp;RUN confirmed EZH2\/H3K27me3 enrichment at key TDGs (\n                      <jats:italic>SLC5A5<\/jats:italic>\n                      ,\n                      <jats:italic>NKX2\u20101<\/jats:italic>\n                      ,\n                      <jats:italic>TSHR<\/jats:italic>\n                      ,\n                      <jats:italic>FOXE1<\/jats:italic>\n                      ,\n                      <jats:italic>TPO<\/jats:italic>\n                      ). Pharmacological inhibition of EZH2 with EPZ6438 reactivated TDG expression in RAS and BRAF\u2010mutated ATC cell lines and partially restored iodide uptake. Co\u2010treatment with the MEK1\/2 inhibitor U0126 further enhanced TDG expression, consistent with MAPK\u2010dependent regulation of EZH2. These findings reveal EZH2 as a mediator of ATC dedifferentiation and highlight its inhibition as a potential strategy to restore thyroid function and sensitize tumors to radioiodine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                        <jats:caption>\n                          <jats:title>Impact statement<\/jats:title>\n                        <\/jats:caption>\n                        <jats:p>This study reveals how EZH2\u2010driven epigenetic remodeling controls thyroid cell dedifferentiation and loss of iodide uptake in anaplastic thyroid cancer. Our findings provide new mechanistic insights and highlight an FDA\u2010approved drug with repurposing potential, advancing both anaplastic thyroid cancer biology research and therapeutic perspectives.<\/jats:p>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/1873-3468.70207","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:03:05Z","timestamp":1761663785000},"page":"215-225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting\n                    <scp>EZH2<\/scp>\n                    reverses thyroid cell dedifferentiation and enhances iodide uptake in anaplastic thyroid cancer"],"prefix":"10.1002","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6405-0635","authenticated-orcid":false,"given":"Diego Claro","family":"de 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