Calcium dysregulation amplifies fibrotic responses to TGFβ in human Friedreich's ataxia fibroblasts.

Friedreich's ataxia (FA) is an inherited disease caused by loss of frataxin ( FXN ) and characterized by neurodegeneration and fatal cardiomyopathy. 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 TGFβ-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 ( CCN2 , NOX4 ) and suppression of anti-fibrotic ( CCN3 ) genes, which were inversely correlated with residual FXN . Mechanistically, FA fibroblasts exhibited elevated cytosolic Ca and strongly downregulated expression of the Na-Ca exchanger NCX1, which directly correlated with FXN . Furthermore, NCX1 inhibition in control fibroblasts recapitulated FA Ca phenotypes, whereas NCX1 transduction in FA fibroblasts normalized Ca dynamics and blunted CCN2 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.