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Cardiac fibrosis contributes to cardiomyopathy by stiffening the heart wall, yet the underlying mechanisms remain unknown. Here, we investigated pro-fibrotic predisposition in FA patient-derived fibroblasts, focusing on the role of cytosolic calcium (Ca) in TGF\u03b2-driven fibroblast-to-myofibroblast transition (FMT). We found pro-fibrotic transcriptional priming in FA fibroblasts, alongside elevated expression of genes controlled by the Ca-responsive transcription factor NFAT. Upon FMT, FA myofibroblasts showed amplified induction of pro-fibrotic (\n                  <jats:italic>CCN2<\/jats:italic>\n                  ,\n                  <jats:italic>NOX4<\/jats:italic>\n                  ) and suppression of anti-fibrotic (\n                  <jats:italic>CCN3<\/jats:italic>\n                  ) genes, which were inversely correlated with residual\n                  <jats:italic>FXN<\/jats:italic>\n                  . Mechanistically, FA fibroblasts exhibited elevated cytosolic Ca and strongly downregulated expression of the Na-Ca exchanger NCX1, which directly correlated with\n                  <jats:italic>FXN<\/jats:italic>\n                  . Furthermore, NCX1 inhibition in control fibroblasts recapitulated FA Ca phenotypes, whereas\n                  <jats:italic>NCX1<\/jats:italic>\n                  transduction in FA fibroblasts normalized Ca dynamics and blunted\n                  <jats:italic>CCN2<\/jats:italic>\n                  induction in FMT. These findings highlight NCX1 as a modulator of fibrotic reprogramming in FA and identify Ca dyshomeostasis as an intrinsic mechanism of fibrosis that could be targeted therapeutically.\n                <\/jats:p>","DOI":"10.64898\/2026.09.21.753166","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:25:14Z","timestamp":1790339114000},"source":"Crossref","is-referenced-by-count":0,"title":["Calcium dysregulation amplifies fibrotic responses to TGF\u03b2 in human Friedreich\u2019s ataxia fibroblasts"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6557-0539","authenticated-orcid":false,"given":"Anna","family":"Stepanova","sequence":"first","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-6933","authenticated-orcid":false,"given":"Hibiki","family":"Kawamata","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3893-1348","authenticated-orcid":false,"given":"Giovanni","family":"Manfredi","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092820500594000_2026.09.21.753166v1.1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00188"},{"key":"2026092820500594000_2026.09.21.753166v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00264"},{"key":"2026092820500594000_2026.09.21.753166v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.10.016"},{"key":"2026092820500594000_2026.09.21.753166v1.4","doi-asserted-by":"crossref","unstructured":"Badia-I-Mompel P , V\u00e9lez Santiago J , Braunger J , Geiss C , Dimitrov D , M\u00fcller-Dott S , Taus P , Dugourd A , Holland CH , Ramirez Flores RO , et al (2022) decoupleR: ensemble of computational methods to infer biological activities from omics data. 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