Ferroptosis and Cardiac Injury: Mechanisms and Therapeutic Targets

Ferroptosis, an iron-dependent regulated form of cell death marked by lipid peroxidation and mitochondrial shrinkage, has emerged as a critical contributor to cardiovascular injury. It drives cardiomyocyte loss in myocardial infarction, diabetic cardiomyopathy, and heart failure. Triggered by excessive reactive oxygen species (ROS), lipid peroxidation, and impaired antioxidant defenses, ferroptosis promotes inflammation and fibrosis, exacerbating adverse cardiac remodeling. Iron overload and mitochondrial dysfunction further amplify this process. Key enzymes such as GPX4 and FSP1 act as protective regulators by detoxifying lipid peroxides and maintaining redox balance. Importantly, ferroptotic cardiomyocytes release damage-associated molecular patterns (DAMPs), sustaining local inflammation and activating fibroblasts, linking cell death directly to fibrotic progression. Understanding how ferroptosis interacts with integrin signaling, ROS, and inflammatory pathways may provide novel therapeutic strategies to limit cardiac injury and maladaptive remodeling.



Despite growing recognition of its contribution to myocardial infarction, cardiomyopathy, and heart failure, the molecular and cellular networks connecting ferroptosis with inflammation and fibrosis remain incompletely understood. This research topic aims to bridge this knowledge gap by uncovering how ferroptosis contributes to cardiac injury, remodeling, and maladaptive repair. We seek studies that elucidate the molecular regulators and signaling pathways driving ferroptosis in cardiomyocytes, fibroblasts, and endothelial cells, as well as its intersection with oxidative stress, integrin signaling, and immune activation. By integrating insights from basic, translational, and pharmacological research, this collection aims to identify therapeutic targets such as antioxidants, iron chelators, and GPX4/FSP1 modulators to mitigate ferroptosis-induced inflammation and fibrosis. Ultimately, this issue will foster new strategies to preserve cardiac function and improve cardiovascular outcomes.



This Research Topic aims to provide a comprehensive exploration of the multifaceted roles of ferroptosis in cardiovascular disease. It will highlight ferroptosis in conditions such as myocardial ischemia-reperfusion injury, atrial fibrillation, aortic dissection, cardiometabolic disorders, and drug-induced cardiac injury. We aim to elucidate the complex crosstalk between oxidative stress, inflammation, fibrosis, cell clearance mechanisms, and ferroptosis in the heart. Studies focused on iron accumulation, Fenton reactions, and key molecular regulators in cardiomyocytes including GPX4, ACSL4, SLC7A11, ACSL1-6, RPL8, IREB2, ATP5G3, TTC35, CS, and ACSF2 alongside pharmacological modulators such as resveratrol and semaglutide are particularly encouraged. Investigations into signaling pathways, including MAPK/ERK, the PKC-S100A9 axis, and other relevant pathways, are welcome. Research examining how ferroptosis drives inflammation, particularly via the release and exposure of damage-associated molecular patterns (DAMPs) that activate innate and adaptive immune responses and other yet to-be-characterized inflammatory pathways, will be emphasized. Additionally, studies addressing ECM–integrin signaling in fibroblast activation, metabolic reprogramming, and ROS-driven lipid peroxidation that sensitize cells to ferroptosis are encouraged. Novel in vivo and in vitro models and therapeutic strategies including antioxidants, iron chelators, and GPX4/FSP1 modulators will be highlighted for their potential to mitigate cardiac injury, limit inflammation, and reverse fibrosis.