Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis

TLDR

Iron homeostasis is critical for cardiac function, and both deficiency and overload contribute to cardiomyopathy, yet the specific role of ferritin H in heart cells remains unclear. The study aimed to determine the functional role of ferritin H in cardiac iron regulation and disease. Conditional knockout mice lacking ferritin H in myocytes or cardiomyocytes were generated by crossing Fth‑floxed mice with MCK‑Cre or Myh6‑Cre lines. Loss of ferritin H in cardiomyocytes lowers cardiac iron, elevates oxidative stress, and predisposes to ferroptosis‑driven hypertrophic cardiomyopathy, which is exacerbated by a high‑iron diet but can be rescued by ferrostatin‑1 or cardiomyocyte‑specific Slc7a11 overexpression, demonstrating ferritin’s protective role against cardiac ferroptosis and heart failure.

Abstract

Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown.To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease.Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis.Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.