Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis
Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis
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DOI：
10.1021/jacs.2c06804
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发表时间：
2022-08-17
影响因子：
15
通讯作者：
Pratt, Derek A.
中科院分区：
文献类型：
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作者：
Wu, Zijun;Khodade, Vinayak S.;Pratt, Derek A.
氢过硫化物（RSSH）被认为在体内发挥重要作用，包括作为破坏性氧化剂和亲电子试剂的清除剂。 α 效应使 RSSH 不仅是比硫醇 (RSH) 更好的亲核试剂，而且是更有效的氢原子转移剂。由于 HAT 是磷脂过氧化和相关铁死亡细胞死亡最有效的小分子抑制剂的作用机制，因此我们研究了它们在这方面的反应性。使用荧光抑制自动氧化 (FENIX) 方法，我们发现 RSSH 对磷脂衍生的过氧自由基具有高度反应性 (kinh = 2 x 105 M-1 s(-1))，相当于迄今为止发现的最有效的铁死亡抑制剂。 RSSH 在生理条件下快速自反应产生的相关（多）硫化物产物（例如二硫化物、三硫化物、H2S）基本上不具有反应性，但可以原位产生 RSSH 的组合（即多硫化物与 H2S 或硫醇与 H2S2）是有效的。由设计的前体原位生成 RSSH，通过分子内取代或水解释放 RSSH，通过最大限度地减少有害的自反应来提高 RSSH 的自由基捕获效率。对结构-反应性关系的简要调查使得设计出更有效的新前体成为可能。 RSSH 及其前体的反应性从（磷酸）脂质双层转化为细胞培养物（小鼠胚胎成纤维细胞），在细胞培养物中发现它们可以抑制由谷胱甘肽过氧化物酶 4 (GPX4) 失活或编码其基因缺失引起的铁死亡。这些结果表明，RSSH 及其生物合成途径可能与最近发现的 FSP1/泛醌和 GCH1/BH4/DHFR 系统一起充当铁死亡抑制系统。
Hydropersulfides (RSSH) are believed to serve important roles in vivo, including as scavengers of damaging oxidants and electrophiles. The alpha-effect makes RSSH not only much better nucleophiles than thiols (RSH), but also much more potent H-atom transfer agents. Since HAT is the mechanism of action of the most potent small-molecule inhibitors of phospholipid peroxidation and associated ferroptotic cell death, we have investigated their reactivity in this context. Using the fluorescence-enabled inhibited autoxidation (FENIX) approach, we have found RSSH to be highly reactive toward phospholipid-derived peroxyl radicals (kinh = 2 x 105 M-1 s(-1)), equaling the most potent ferroptosis inhibitors identified to date. Related (poly)sulfide products resulting from the rapid self-reaction of RSSH under physiological conditions (e.g., disulfide, trisulfide, H2S) are essentially unreactive, but combinations from which RSSH can be produced in situ (i.e., polysulfides with H2S or thiols with H2S2) are effective. In situ generation of RSSH from designed precursors which release RSSH via intramolecular substitution or hydrolysis improve the radical-trapping efficiency of RSSH by minimizing deleterious self-reactions. A brief survey of structure-reactivity relationships enabled the design of new precursors that are more efficient. The reactivity of RSSH and their precursors translates from (phospho)lipid bilayers to cell culture (mouse embryonic fibroblasts), where they were found to inhibit ferroptosis induced by inactivation of glutathione peroxidase-4 (GPX4) or deletion of the gene encoding it. These results suggest that RSSH and the pathways responsible for their biosynthesis may act as a ferroptosis suppression system alongside the recently discovered FSP1/ubiquinone and GCH1/BH4/DHFR systems.