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

Myocardial infarction (MI) triggers dynamic tissue remodeling in which fibroblast activation critically determines scar formation and long-term cardiac function. Although iron dysregulation has been implicated in acute myocardial injury, its role in non-cardiomyocyte remodeling remains incompletely understood. Here, we integrated cross-species transcriptomics, spatial transcriptomics, single-cell RNA sequencing, and functional studies to investigate iron metabolic remodeling after MI. We found that ferritin heavy chain (Fth1) was robustly induced in the infarct region during the proliferative phase after MI and was predominantly localized to macrophages and fibroblasts. Single-cell trajectory analysis revealed that high Fth1 expression characterized early or inflammatory fibroblast states, whereas progressive Fth1 downregulation accompanied differentiation into extracellular matrix-producing myofibroblasts. Functionally, ferritin depletion promoted fibroblast activation in both neonatal rat and adult mouse cardiac fibroblasts, accompanied by expansion of the intracellular labile iron pool (LIP) and enhanced pro-fibrotic gene expression. Mechanistically, intracellular iron chelation suppressed fibroblast activation and was associated with alterations in FoxO1-related 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.