From iron-driven cell death to clot formation: The emerging role of ferroptosis in thrombogenesis

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress, has emerged as a novel contributor to thrombogenesis. This narrative literature review explores the mechanistic intersections between ferroptosis and thrombosis, highlighting shared pathways, including iron overload and endothelial dysfunction. Evidence suggests that ferroptosis disrupts endothelial integrity and amplifies procoagulant signals, such as tissue factor expression and phosphatidylserine externalization. Hypoxia-induced HIF-1α activation promotes iron accumulation and metabolic reprogramming, creating a microenvironment conducive to ferroptosis and thrombus formation. Furthermore, key mediators such as the transferrin receptor (TFRC), lipocalin-2 (LCN2), and thrombospondin-1 (THBS1) orchestrate a ferroptosis-driven prothrombotic pathway through redox imbalance and vascular inflammation. The review also discusses therapeutic implications, noting that ferroptosis inhibitors (e.g., liproxstatin-1, deferoxamine) demonstrate protective effects in thrombotic models by restoring endothelial homeostasis and limiting coagulation. However, inducing ferroptosis in oncology may paradoxically elevate thrombotic risk, underscoring the need for balanced therapeutic strategies. • Ferroptosis links iron overload and lipid peroxidation to thrombus formation. • HIF-1α signaling connects hypoxia, ferroptosis, and procoagulant activity. • TFRC and LCN2 drive endothelial ferroptosis and thrombogenic signaling. • Ferroptosis inhibitors reduce thrombus size and restore endothelial function.