Our study suggests that cytosolic Ca regulation modifies profibrotic
stimulation in FA. We propose the following mechanism for intrinsic profibrotic bias in
human FA fibroblasts: NCX1 downregulation contributes to slower cytosolic Ca
clearance, thereby sustaining Ca-dependent signaling and consequently increased
expression of CCN2 and other profibrotic factors. If validated in FA heart, our findings
would identify NCX1-mediated Ca extrusion in fibroblasts as a potential therapeutic target
to mitigate fibrosis that contributes to lethal cardiomyopathy in FA patients.