Secondary ferroptosis promotes thrombogenesis after venous injury in rats

Iron accumulation significantly accelerates thrombosis after vascular injury. The role of the ferroptosis pathway induced by iron overload in thrombosis has not been previously elucidated. In this study, we answer certain obscure questions regarding the contribution of ferroptosis to deep vein thrombosis (DVT) and explore new and potential mechanisms of thrombogenesis.

After inducing mechanical injury to establish a DVT model with rats, liproxstatin-1 (an inhibitor of ferroptosis) was administered to inhibit ferroptosis in the injured venous rat tissue. Thrombus characteristics and ferroptosis biomarkers were evaluated. Proteomic and comprehensive bioinformatics analyses were performed to elucidate the potential mechanism by which injury affects DVT.

Ferroptosis is characteristic of injured venous tissues and mainly manifests in tissue as increased reactive oxygen species (ROS), malondialdehyde (MDA), and iron levels and decreased glutathione (GSH) level; mitochondrial membrane potential disruption; and abnormal expression of protein markers. In this study, administration of liproxstatin-1 before injury did not affect the rate of trauma-induced thrombogenesis but affected DVT progression, as indicated by reduced thrombus size and attenuated hypercoagulability. Differences between control, DVT and liproxstatin-1 treatment predominantly affected pathways of complement/coagulation cascades, glycolysis/gluconeogenesis, ferroptosis and so on. Transferrin receptor 1 (TFRC), lipocalin 2 (LCN2) and thrombospondin 1 (THBS1) were identified as hub proteins in ferroptosis and coagulation cascades.

Ferroptosis is involved in mechanical injury-induced DVT. Inhibition of ferroptosis through liproxstatin-1 treatment can ameliorate symptoms. These findings suggest a previously unknown mechanism by which ferroptosis induced by iron accumulation contributes to thrombosis.