Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden; Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, United States.
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Redox Biol. 2023 Jun;62:102703. doi: 10.1016/j.redox.2023.102703. Epub 2023 Apr 17.
Ferroptosis is defined as cell death triggered by iron-dependent lipid peroxidation that is preventable by antioxidant compounds such as ferrostatin-1. Endogenous suppressors of ferroptosis include FSP-1 and the selenoprotein GPX4, the latter of which directly enzymatically reduces lipid hydroperoxides. Small molecules that trigger ferroptosis include RSL3, ML162, and ML210; these compounds are often used in studies of ferroptosis and are generally considered as GPX4 inhibitors. Here, we found that RSL3 and ML162 completely lack capacity of inhibiting the enzymatic activity of recombinant selenoprotein GPX4. Surprisingly, these compounds were instead found to be efficient inhibitors of another selenoprotein, TXNRD1. Other known inhibitors of TXNRD1, including auranofin, TRi-1 and TRi-2, are also efficient inducers of cell death but that cell death could not be suppressed with ferrostatin-1. Our results collectively suggest that prior studies using RSL3 and ML162 may need to be reevaluated in the context of ferroptosis with regards to additional enzyme targets and mechanisms of action that may be involved.
铁死亡是一种由铁依赖性脂质过氧化引发的细胞死亡，可以被抗氧化化合物如 ferrostatin-1 所预防。铁死亡的内源性抑制因子包括 FSP-1 和硒蛋白 GPX4，后者直接酶促还原脂质过氧化物。引发铁死亡的小分子包括 RSL3、ML162 和 ML210；这些化合物通常用于铁死亡的研究，通常被认为是 GPX4 的抑制剂。在这里，我们发现 RSL3 和 ML162 完全缺乏抑制重组硒蛋白 GPX4 酶活性的能力。令人惊讶的是，这些化合物反而被发现是另一种硒蛋白 TXNRD1 的有效抑制剂。其他已知的 TXNRD1 抑制剂，包括 auranofin、TRi-1 和 TRi-2，也是有效的细胞死亡诱导剂，但铁死亡不能被 ferrostatin-1 抑制。我们的结果表明，以前使用 RSL3 和 ML162 的研究可能需要重新评估，在铁死亡的背景下，考虑可能涉及的其他酶靶标和作用机制。
