Selenium (Se) is an essential trace element for maintaining cardiovascular health. Although Se deficiency is associated with various vascular diseases, its precise role in venous endothelial injury remains unclear. Therefore, we established the porcine model of Se deficiency in vivo and used SUVECs in vitro to investigate the potential mechanisms of Se deficiency-induced venous inflammatory injury. The results demonstrated that Se deficiency activated ferritinophagy in porcine vein, accompanied by lipid peroxidation and mitochondrial dynamics disorder, ultimately leading to ferroptosis and the release of pro-inflammatory cytokines. In vitro experiments demonstrated that pharmacological inhibition of autophagy or nuclear receptor coactivator 4 (NCOA4) knockout reduced intracellular iron levels and attenuated ferroptosis, suggesting that NCOA4-mediated ferritinophagy was essential for the ferroptosis induced by Se deficiency. Furthermore, Se deficiency upregulated the expression of sideroflexin-1 (SFXN1) in porcine vein. We further found that NCOA4 knockout or treatment with the iron chelator deferoxamine (DFO) markedly downregulated Se deficiency-induced SFXN1 expression, indicating that Fe²⁺ released from NCOA4-mediated ferritinophagy activates SFXN1. What's more, SFXN1 knockout alleviated mitochondrial iron overload, decreased mitochondrial reactive oxygen species (mtROS) and lipid peroxidation, and inhibited ferroptosis. Notably, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively alleviated Se deficiency-induced porcine phlebitis, thereby linking ferroptosis to vascular inflammation. In addition, AMPK-mTOR pathway plays a pivotal role in orchestrating Se deficiency-induced ferritinophagy and subsequent ferroptosis. Overall, these findings elucidate novel mechanisms by which Se deficiency induces venous endothelial injury, and identify ferritinophagy and SFXN1-mediated mitochondrial iron transport as potential therapeutic targets for cardiovascular pathologies associated with Se deficiency.
