PRDX6 dictates ferroptosis sensitivity by directing cellular selenium mobilization

Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis and prevents unrestrained (phospho)lipid peroxidation by directly reducing phospholipid hydroperoxides (PLOOH) to their corresponding alcohols. However, it remains unclear whether other phospholipid peroxidases can also contribute to ferroptosis prevention, albeit to a varying degree. Here we show that cells lacking GPX4 still exhibit substantial PLOOH reduction capacity, arguing for the presence of alternative PLOOH peroxidases. Mechanistically, we uncover that PRDX6 facilitates intracellular selenium handling, which is crucial for selenium incorporation into selenoproteins, including GPX4.

硒依赖性谷胱甘肽过氧化物酶4（Selenium-dependent glutathione peroxidase 4, GPX4）是铁死亡（ferroptosis）的核心调控因子，可通过将磷脂氢过氧化物（phospholipid hydroperoxides, PLOOH）直接还原为相应醇类，从而抑制失控的（磷酸）脂质过氧化（(phospho)lipid peroxidation）进程。然而，目前尚不清楚是否存在其他磷脂过氧化物酶，也能以不同程度参与铁死亡的抑制过程。本研究证实，缺失GPX4的细胞仍具备显著的PLOOH还原能力，这提示存在替代性的磷脂氢过氧化物过氧化物酶。机制层面，本研究揭示过氧还蛋白6（Peroxiredoxin 6, PRDX6）可调控细胞内硒的代谢处理，这对于包括GPX4在内的硒蛋白（selenoproteins）的硒掺入过程至关重要。