Targeting selenocysteine metabolism as a novel ferroptosis inducing strategy

Ferroptosis is a form of non-apoptotic cell death driven by iron-dependent phospholipid peroxidation and has emerged as a potential therapeutic strategy in cancer treatment. A crucial factor determining ferroptosis resistance is the selenoprotein glutathione peroxidase 4 (GPX4), which detoxifies lipid hydroperoxides, thereby preventing cell death. However, direct inhibition of GPX4 poses challenges due to systemic toxicity. Understanding the role of selenocysteine (Sec) metabolism in ferroptosis sensitivity could provide novel therapeutic opportunities as this biological pathway directly regulates the stability of GPX4. This dissertation investigates the regulation of ferroptosis through Sec metabolism, identifying selenoprotein P (SELENOP) and its receptor, low-density lipoprotein receptor-related protein 8 (LRP8), as key determinants of ferroptosis resistance in MYCN-amplified neuroblastoma. Loss of LRP8 disrupts Sec supply, impairing GPX4 synthesis and inducing ferroptosis. Additionally, we uncover an alternative Sec metabolic pathway mediated by peroxiredoxin 6 (PRDX6), that can act independently of the canonical selenocysteine β-lyase (SCLY) route. These findings highlight novel regulatory mechanisms of ferroptosis and propose targeting Sec metabolism as a potential strategy for selectively inducing ferroptosis in cancer therapy.