Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S⁰) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for S⁰ biosynthesis, cysteine can support ferroptosis resistance independently of the canonical GPX4 pathway. Our results further suggest that hydropersulfides terminate radical chain reactions through the formation and self-recombination of perthiyl radicals. The autocatalytic regeneration of hydropersulfides may explain why low micromolar concentrations of persulfides suffice to produce potent cytoprotective effects on a background of millimolar concentrations of glutathione. We propose that increased S⁰ biosynthesis is an adaptive cellular response to radical-driven lipid peroxidation, potentially representing a primordial radical protection system.

铁死亡是一种由自由基驱动的脂质过氧化引起的细胞死亡，导致膜损伤和破裂。在这里，我们表明酶促产生的硫烷硫 (S ⁰ ) 物种，特别是氢过硫化物，清除内源性产生的自由基，从而抑制脂质过氧化和铁死亡。^{通过为 S 0}提供硫在生物合成中，半胱氨酸可以独立于经典 GPX4 途径支持铁死亡抗性。我们的结果进一步表明，氢过硫化物通过过硫基自由基的形成和自重组终止自由基链反应。氢过硫化物的自催化再生可以解释为什么低微摩尔浓度的过硫化物足以在毫摩尔浓度的谷胱甘肽背景下产生有效的细胞保护作用。我们提出增加的 S ⁰生物合成是对自由基驱动的脂质过氧化反应的适应性细胞反应，可能代表原始自由基保护系统。