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

ABSTRACT: 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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE330351 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Signal-induced proliferation-associated gene 1 (Sipa1) is known as a specific Rap1 GTPase-activating protein that negatively regulates Rap1 signaling. Although Sipa1 has been extensively studied in cancer research, its role in the wound healing response after myocardial infarction (MI) remains unexplored. To investigate the role of endogenous Sipa1 in MI, we performed permanent left anterior descending artery ligation in both Sipa1 knockout mice and their control littermates. Bone marrow transplantation, flow cytometry, cell sorting, and transcriptomic analysis were conducted to identify the cellular source of Sipa1 in the infarcted heart. The role of cardiac fibroblast-derived Sipa1 during MI was examined using Sipa1 deletion approaches, specifically in cardiac fibroblasts, in vivo and in vitro. Mice deficient in Sipa1 exhibited improved post-MI survival and cardiac function, along with attenuated expression of inflammatory mediators and diminished accumulation of Ly6Chigh monocytes and CCR2+ macrophages in the infarcted heart. Although Sipa1 was broadly expressed in the heart, cardiac fibroblasts were responsible for the Sipa1-induced deleterious phenotype as demonstrated by cardiac fibroblast-specific Sipa1 conditional knockout mice, which averted excessive inflammation and adverse cardiac remodeling following MI. Mechanistically, Sipa1 promotes the production of CCL2, CCL7 and granulocyte/macrophage colony-stimulating factor in the cardiac fibroblasts early after MI via a non-canonical RasGRP2-Ras-JNK signaling pathway, irrespective of canonical Rap1, thereby facilitating the accumulation and activation of inflammatory monocytes and macrophages. These results identify a previously unknown fibroblast-immune axis characterized by Sipa1, which initiates excessive inflammation and leads to poor outcomes after MI. Targeting Sipa1 offers a potential novel therapeutic strategy to optimize post-MI wound healing response, thereby preventing the development of chronic ischemic heart failure.

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

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