From ER and mitochondria to contact sites: integrated regulation of ferroptosis in cardiovascular diseases

Iron is a central regulator of cellular redox homeostasis, supporting essential physiological processes. Given its critical biological importance, iron homeostasis is tightly regulated at both the systemic and cellular levels. Ferroptosis is a metabolically regulated, iron-dependent form of cell death characterized by the accumulation of phospholipid hydroperoxides driven by iron-catalyzed redox reactions, ultimately leading to oxidative membrane damage. Accumulating evidence indicates that ferroptosis emerges from the coordinated activity of multiple subcellular organelles rather than from isolated pathways. In this context, the endoplasmic reticulum (ER) and mitochondria have recently been established as key regulators of ferroptotic signaling. Notably, mitochondria-associated membranes (MAMs), by spatially coordinating redox signaling and lipid peroxidation, calcium fluxes, mitochondrial metabolism and lipid remodeling, are increasingly recognized as central hubs within the ferroptotic cascade, acting as modulators of cellular susceptibility to ferroptosis and as key sites of its execution. Owing to its strong dependence on mitochondrial oxidative phosphorylation, the heart is particularly sensitive to perturbations in iron homeostasis. Notably, growing evidence supports a pathogenic role for ferroptosis in cardiovascular diseases (CVDs), linking iron-dependent oxidative stress to cardiomyocyte dysfunction and tissue injury. Accordingly, ferroptosis has emerged as a potential therapeutic target in cardiovascular pathology. This review examines how ER and mitochondrial dysfunction contribute to ferroptotic signaling in CVDs and discusses the hypothesis that MAMs may function as central regulatory interfaces coordinating these processes. Elucidating these mechanisms is essential for the development of novel therapeutic strategies aimed at modulating ferroptosis and limiting CVDs progression.