Ferroptosis is a unique form of cell death caused by excessive iron-dependent lipid peroxidation. The level of the anabolic reductant NADPH is a biomarker of ferroptosis sensitivity. However, specific regulators that detect cellular NADPH levels, thereby modulating downstream ferroptosis cascades, are largely unknown. We show here that the transmembrane endoplasmic reticulum MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This interaction upregulates the E3 ligase activity of MARCHF6, thus downregulating ferroptosis. We also found that MARCHF6 mediates the degradation of the key ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and peri-natal lethality of Marchf6^–/– mice. Together, these findings identify MARCHF6 as a previously unknown NADPH sensor in the ubiquitin system and a crucial regulator of ferroptosis.

铁死亡是由过度的铁依赖性脂质过氧化引起的一种独特的细胞死亡形式。合成代谢还原剂 NADPH 的水平是铁死亡敏感性的生物标志物。然而，检测细胞 NADPH 水平从而调节下游铁死亡级联反应的特定调节剂在很大程度上是未知的。我们在这里显示跨膜内质网 MARCHF6 E3 泛素连接酶通过其 C 末端调节区识别 NADPH。这种相互作用上调了 MARCHF6 的 E3 连接酶活性，从而下调了铁死亡。我们还发现 MARCHF6 介导了关键的铁死亡效应因子 ACSL4 和 p53 的降解。此外，抑制铁死亡挽救了 MARCHF6 缺陷肿瘤的生长和 Marchf6 的围产期致死率– ^/–老鼠。总之，这些发现将 MARCHF6 确定为泛素系统中以前未知的 NADPH 传感器和铁死亡的关键调节剂。