Ferroptosis, a new form of non-apoptotic, regulated cell death characterized by iron dependency and lipid peroxidation, is involved in many pathological conditions such as neurodegenerative diseases, heart ischemia/reperfusion injury, acute renal failure, and cancer. While metabolic dysfunctions can lead to excessive lipid peroxidation culminating in ferroptotic cell death, glutathione peroxidase 4 (GPX4) resides in the center of a network that functions to prevent lipid hydroperoxides from accumulation, thereby suppressing ferroptosis. Indeed, RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice. Similarly, erastin and other system Xc⁻ inhibitors can deplete intracellular glutathione required for GPX4 function, leading to lipid peroxidation and ferroptosis. As therapy-resistant cancer cells are sensitive to GPX4-targeted therapeutic regimens, the agents capable of inducing ferroptosis hold great promises to improve current cancer therapy. This review will outline the molecular basis of ferroptosis, but focus on the strategies and the agents developed in recent years for therapeutic induction of ferroptosis. The potentials of these ferroptosis-inducing agents, which include system Xc⁻ inhibitors, GPX4 inhibitors, and iron-based nanoparticles, in cancer therapy will be subsequently discussed.

铁死亡是一种以铁依赖和脂质过氧化为特征的非凋亡性、受调节的细胞死亡的新形式，与许多病理状况有关，例如神经退行性疾病、心脏缺血/再灌注损伤、急性肾功能衰竭和癌症。虽然代谢功能障碍会导致过度的脂质过氧化，最终导致细胞铁死亡，但谷胱甘肽过氧化物酶 4 (GPX4) 位于网络的中心，其作用是防止脂质氢过氧化物的积累，从而抑制铁死亡。事实上，RSL3 和其他小分子 GPX4 抑制剂不仅可以在培养的癌细胞中诱导铁死亡，还可以在植入小鼠的肿瘤异种移植物中诱导铁死亡。同样，erastin 和其他系统 Xc ^-抑制剂可以耗尽 GPX4 功能所需的细胞内谷胱甘肽，导致脂质过氧化和铁死亡。由于耐药癌细胞对 GPX4 靶向治疗方案敏感，因此能够诱导铁死亡的药物有望改善当前的癌症治疗。本综述将概述铁死亡的分子基础，但重点关注近年来开发的用于治疗性诱导铁死亡的策略和药物。随后将讨论这些铁死亡诱导剂（包括系统 Xc ^-抑制剂、GPX4 抑制剂和铁基纳米颗粒）在癌症治疗中的潜力。