ROLE OF THE RETROMER COMPLEX IN FERROPTOSIS

Abstract

Ferroptosis is a recently discovered mechanism of regulated cell death that occurs due to the excessive peroxidation of plasma membrane lipids. This reaction depends on catalysis by intracellular ferrous iron (Fe2+) and is counteracted by antioxidant defense systems. Transferrin receptor 1 (TFRC) is an essential contributor to intracellular iron metabolism because it facilitates the import of extracellular iron. Unsurprisingly, the overexpression of TFRC is an accurate marker of ferroptosis. Recent findings highlight the potential involvement of TFRC recycling in ferroptosis regulation. In particular, sorting nexin 3 (SNX3), a component of the retromer complex responsible for retrograde trafficking of TFRC, has been implicated in ferroptosis-induced cardiomyopathy. This makes SNX3 a potential target for therapeutic intervention or a marker of ferroptosis sensitivity. SNX3 expression is correlated with increased iron burden and epithelial–mesenchymal transition in breast cancer patients. Therefore, we hypothesize that SNX3 could play a role in promoting cancer development by increasing the amount of intracellular iron. Moreover, SNX3 might also sensitize cancer cells to ferroptosis-inducing agents.