The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1.
The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1.
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DOI：
10.1016/j.redox.2023.102703
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发表时间：
2023-06
期刊：
影响因子：
11.4
通讯作者：
Arner, Elias S. J.
中科院分区：
文献类型：
--
作者：
Cheff, Dorian M.;Huang, Chuying;Scholzen, Karoline C.;Gencheva, Radosveta;Ronzetti, Michael H.;Cheng, Qing;Hall, Matthew D.;Arner, Elias S. J.
铁死亡被定义为由铁依赖性脂质过氧化引发的细胞死亡，这种死亡可以通过抗氧化剂化合物（例如 Ferrostatin-1）来预防。铁死亡的内源性抑制剂包括 FSP-1 和硒蛋白 GPX4，后者直接酶促减少脂质氢过氧化物。引发铁死亡的小分子包括 RSL3、ML162 和 ML210；这些化合物经常用于铁死亡的研究，通常被认为是 GPX4 抑制剂。在此，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，包括金诺芬、TRi-1 和 TRi-2，也是细胞死亡的有效诱导剂，但 Ferrostatin-1 无法抑制细胞死亡。我们的结果总体表明，之前使用 RSL3 和 ML162 的研究可能需要在铁死亡的背景下重新评估可能涉及的其他酶靶点和作用机制。
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.
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影响因子：
11.4
作者：
Sabatier P;Beusch CM;Gencheva R;Cheng Q;Zubarev R;Arnér ESJ
通讯作者：
Arnér ESJ
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4.8
作者：
Gromer, S;Arscott, LD;Becker, K
通讯作者：
Becker, K
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M
影响因子：
11.4
作者：
Schwarz, Maria;Loeser, Alina;Cheng, Qing;Wichmann-Costaganna, Mareike;Schaedel, Patrick;Werz, Oliver;Arner, Elias S. J.;Kipp, Anna P.
通讯作者：
Kipp, Anna P.