Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity.

中文翻译：

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PRDX6 通过指导细胞硒的利用来决定铁死亡敏感性


硒依赖性谷胱甘肽过氧化物酶 4 （GPX4） 是铁死亡的守护者，通过减少磷脂氢过氧化物 （PLOOH） 来防止不受约束的（磷酸化）脂质过氧化。然而，其他磷脂过氧化物酶在铁死亡保护中的作用仍不清楚。我们表明，缺乏 GPX4 的细胞仍然表现出显着的 PLOOH 降低能力，这表明替代 PLOOH 过氧化物酶的贡献。通过仔细检查潜在的候选者，我们发现虽然过氧化物还原蛋白 6 （PRDX6） 的过表达，一种具有降低 PLOOH 活性的巯基特异性抗氧化酶，未能预防铁死亡，但其基因丢失使癌细胞对铁死亡敏感。从机制上讲，我们发现 PRDX6 除了其已知的过氧化物酶活性之外，还充当硒受体蛋白，促进细胞内硒的利用和硒的有效掺入硒蛋白，包括 GPX4。其生理意义表现为 Prdx6 缺陷小鼠大脑中 GPX4 表达降低和小鼠 PRDX6 缺陷肿瘤异种移植物中对铁死亡敏感性增加。我们的研究强调 PRDX6 是指导细胞硒利用和决定铁死亡敏感性的关键参与者。