Higuchi Masayoshi, Williams August F, Stuhlfire Anna E, Nguyen Ariel H, Gervasio David A G, Turkal Claire E, Chon Suejean, Hangauer Matthew J
Department of Dermatology, School of Medicine, University of California San Diego, San Diego, CA, USA.
Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
Sci Adv. 2026 Jan 2;12(1):eaea8771. doi: 10.1126/sciadv.aea8771.
Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis, but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione, and various ferroptosis-suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is down-regulated in multiple persister cell types, and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely on residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition down-regulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induces reactive oxygen species and sensitizes multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.
在致癌基因靶向治疗后存活下来的癌症持久性细胞对铁死亡敏感，但对这种脆弱性的机制理解仍然有限。在这里，我们发现，虽然铁、谷胱甘肽和各种抑制铁死亡的酶的水平在不同类型的持久性细胞中有所不同，但铁死亡抑制蛋白1（FSP1）在多种类型的持久性细胞中表达下调，并且在谷胱甘肽过氧化物酶4（GPX4）抑制后存活下来的持久性细胞依赖残余的FSP1来存活。此外，在GPX4抑制后存活下来的持久性细胞下调氧化磷酸化，氧化磷酸化是持久性细胞铁死亡所需的线粒体活性氧的关键来源。我们还发现，用组蛋白去乙酰化酶抑制剂处理持久性细胞会诱导活性氧，并使多种类型的持久性细胞对GPX4抑制敏感。总之，这些发现表明FSP1和组蛋白去乙酰化酶抑制持久性细胞的铁死亡。
