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Cardiomyopathy is the leading cause of mortality in individuals with FRDA. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three individuals with FRDA, each paired with an isogenic control line generated through CRISPR\/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored\n                    <jats:italic>FXN<\/jats:italic>\n                    expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency.\n                    <jats:italic>MEG3<\/jats:italic>\n                    and\n                    <jats:italic>PCDHGA10<\/jats:italic>\n                    were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Functional interrogation of these candidates demonstrated that targeted silencing of\n                    <jats:italic>MEG3<\/jats:italic>\n                    or\n                    <jats:italic>PCDHGA10<\/jats:italic>\n                    in FRDA cardiomyocytes significantly reduced disease\u2011associated cell death without affecting\n                    <jats:italic>FXN<\/jats:italic>\n                    expression. Notably,\n                    <jats:italic>PCDHGA10<\/jats:italic>\n                    silencing also normalized elevated mitochondrial reactive oxygen species, whereas\n                    <jats:italic>MEG3<\/jats:italic>\n                    silencing did not, highlighting gene\u2011specific contributions to FRDA cardiomyocyte survival. Collectively, these findings identify\n                    <jats:italic>MEG3<\/jats:italic>\n                    and\n                    <jats:italic>PCDHGA10<\/jats:italic>\n                    as functionally relevant regulators of FRDA cardiomyocyte pathology.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-09030-3","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:23:58Z","timestamp":1782174238000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Frataxin deficiency drives cardiac dysfunction and transcriptional dysregulation in Friedreich ataxia iPSC model"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9259-8657","authenticated-orcid":false,"given":"Jarmon G.","family":"Lees","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lebei","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren Jie","family":"Phang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Bass-Stringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hei-Yi H.","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony S.","family":"Mukhtar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7408-9453","authenticated-orcid":false,"given":"Alice","family":"P\u00e9bay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirella","family":"Dottori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Corben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Delatycki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Peverill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Wilcox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarny","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Pullin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davis","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill S.","family":"Napierala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Napierala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0442-3655","authenticated-orcid":false,"given":"Shiang Y.","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"9030_CR1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.2217\/nmt-2022-0011","volume":"12","author":"M Keita","year":"2022","unstructured":"Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR. 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