Ferritin-mediated iron homeostasis regulates fibroblast activation and shapes post-infarction cardiac remodeling

Functionally, ferritin depletion promoted fibroblast activation in both neonatal rat and adult mouse cardiac fibroblasts, accompanied by expansion of the intracellular labile iron pool and enhanced profibrotic gene expression. Mechanistically, intracellular iron chelation suppressed fibroblast activation and attenuated FoxO1 signaling–associated transcriptional programs. Notably, temporally targeted treatment with the cell-permeable iron chelator 2,2′-bipyridyl (BPD) during the proliferative phase (days 3–14), but not the acute inflammatory phase (days 0-3), effectively attenuated pathological fibrosis and improved cardiac function after MI.

Transcriptomic profiling further showed that iron chelation modulated both fibroblast activation–associated and inflammatory gene programs within the infarcted myocardium. Collectively, these findings identify ferritin-regulated iron homeostasis as a key determinant of fibroblast plasticity and highlight phase-specific intracellular iron modulation as a potential therapeutic strategy for limiting adverse cardiac remodeling after MI.