Ferroptosis is a form of regulated cell death induced by iron-dependent accumulation of lipid hydroperoxides. Selenoprotein glutathione peroxidase 4 (GPX4) suppresses ferroptosis by detoxifying lipid hydroperoxides via a catalytic selenocysteine (Sec) residue. Sec, the genetically encoded 21^st amino acid, is biosynthesized from a reactive selenium donor on its cognate tRNA^[Ser]Sec. It is thought that intracellular selenium must be delivered ‘safely’ and ‘efficiently’ by a carrier protein owing to its high reactivity and very low concentrations. Here, we identified peroxiredoxin 6 (PRDX6) as a novel selenoprotein synthesis factor. Loss of PRDX6 decreases the expression of selenoproteins and induces ferroptosis via a reduction in GPX4. Mechanistically, PRDX6 increases the efficiency of intracellular selenium utilization by transferring selenium between proteins within the selenocysteyl-tRNA^[Ser]Sec synthesis machinery, leading to efficient synthesis of selenocysteyl-tRNA^[Ser]Sec. These findings highlight previously unidentified selenium metabolic systems and provide new insights into ferroptosis.

铁死亡是一种由铁依赖性脂质氢过氧化物积累诱导的受调节细胞死亡形式。硒蛋白谷胱甘肽过氧化物酶 4 (GPX4) 通过催化硒代半胱氨酸 (Sec) 残基对脂质氢过氧化物进行解毒，从而抑制铁死亡。 Sec 是基因编码的^第21 个氨基酸，由反应性硒供体在其同源 tRNA ^[Ser]Sec上生物合成。人们认为，由于载体蛋白的高反应性和非常低的浓度，细胞内的硒必须通过载体蛋白“安全”和“有效”地输送。在这里，我们将过氧化还原蛋白 6 (PRDX6) 鉴定为一种新型的硒蛋白合成因子。 PRDX6 的缺失会降低硒蛋白的表达，并通过 GPX4 的减少诱导铁死亡。从机制上讲，PRDX6 通过在硒代半胱氨酰-tRNA ^[Ser]Sec合成机器内的蛋白质之间转移硒来提高细胞内硒的利用效率，从而实现硒代半胱氨酰-tRNA ^[Ser]Sec的有效合成。这些发现突出了以前未知的硒代谢系统，并为铁死亡提供了新的见解。