Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q₁₀ (CoQ) recycling for its function of anti–lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition–mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition–mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.

急性髓系白血病 （AML） 细胞对细胞凋亡的抵抗会导致难治性或复发性疾病，与令人沮丧的临床结果相关。铁死亡是一种由铁依赖性脂质过氧化触发的非凋亡细胞死亡模式，已被研究为针对治疗耐药性癌症的潜在治疗方式，但我们对其在 AML 中的作用了解有限。我们研究了 AML 细胞中的铁死亡，并确定其线粒体调节是一种治疗脆弱性。GPX4 敲除诱导 AML 细胞铁死亡，伴有特征性线粒体脂质过氧化，在体外和体内发挥抗 AML 作用。电子传递链 （ETC） 是辅酶 Q₁₀ （CoQ） 循环的主要来源，因为它在线粒体中具有抗脂质过氧化功能。我们发现线粒体特异性 CoQ 有效抑制 GPX4 抑制介导的铁死亡，表明线粒体脂质氧化还原调节 AML 细胞中的铁死亡。一致地，缺乏功能性 ETC 的 Rho0 细胞比对照细胞对 GPX4 抑制介导的线粒体脂质过氧化和铁死亡更敏感。此外，通过线粒体蛋白酶酪蛋白溶解蛋白酶 P （ClpP） 的过度激活降解 ETC 协同增强了 GPX4 抑制的抗 AML 作用。总的来说，我们的研究结果表明，在 AML 细胞中，GPX4 抑制诱导铁死亡，铁死亡受线粒体脂质氧化还原和 ETC 调节。