J Cell Physiol. 2026 Oct;241(10):e70251. doi: 10.1002/jcp.70251.
ABSTRACT
Hemolysis leads to the release of cell-free hemoglobin (Hb) and heme, potent pro-oxidant molecules capable of disrupting iron homeostasis and driving iron-dependent lipid peroxidation. While hemolysis-associated redox injury has been implicated in multiple pathological conditions, its role in cardiac remodeling in teleosts remains largely unexplored. Here, we investigated whether sustained hemolysis induces cardiac hypertrophy in grass carp through heme-mediated ferroptotic injury and delineated the underlying redox-dependent mechanisms. A persistent hemolysis model was established by intraperitoneal administration of phenylhydrazine (PHZ). Histopathological analyses revealed marked ventricular wall thickening accompanied by extensive myocardial fibrosis. Mechanistically, PHZ-induced hemolysis was associated with disrupted iron homeostasis, enhanced lipid peroxidation, and impaired myocardial redox homeostasis, accompanied by mitochondrial ultrastructural abnormalities associated with ferroptotic stress. Pharmacological iron chelation with deferoxamine (DFO) markedly alleviated myocardial hypertrophy, fibrosis, inflammation, and oxidative injury in vivo, supporting an iron-dependent pathological process. In vitro, exposure of H9C2 cardiomyocytes to heme resulted in significant cellular hypertrophy and upregulation of hypertrophy-associated genes, which were substantially attenuated by DFO and the ferroptosis inhibitor ferrostatin-1 (Fer-1), supporting the involvement of iron-dependent lipid peroxidation in cardiomyocyte injury. Collectively, these findings identify hemolysis-derived heme as a critical trigger of iron dysregulation and ferroptosis-associated cardiomyocyte injury, which may contribute to pathological cardiac remodeling in fish. This study establishes a conserved redox-dependent mechanism linking hemolysis to myocardial remodeling in teleosts and provides new mechanistic insights into cardiovascular injury associated with blood-derived oxidative stress.
PMID:42950108 | DOI:10.1002/jcp.70251