BACKGROUND Cancer is one of the major threats to human health and current cancer therapies have been unsuccessful in eradicating it. Ferroptosis is characterized by iron-dependence and lipid hydroperoxides accumulation, and its primary mechanism involves the suppression of system Xc--GSH (glutathione)-GPX4 (glutathione peroxidase 4) axis. Co-incidentally, cancer cells are also metabolically characterized by iron addiction and ROS tolerance, which makes them vulnerable to ferroptosis. This may provide a new tactic for cancer therapy. SCOPE OF REVIEW The general features and mechanisms of ferroptosis, and the basis that makes cancer cells vulnerable to ferroptosis are described. Further, we emphatically discussed that disrupting GSH may not be ideal for triggering ferroptosis of cancer cells in vivo, but directly inhibiting GPX4 and its compensatory members could be more effective. Finally, the various approaches to directly inhibit GPX4 without disturbing GSH were described. MAJOR CONCLUSIONS Targeting system Xc- or GSH may not effectively trigger cancer cells' ferroptosis in vivo the existence of other compensatory pathways. However, directly targeting GPX4 and its compensatory members without disrupting GSH may be more effective to induce ferroptosis in cancer cells in vivo, as GPX4 is essential in preventing ferroptosis. GENERAL SIGNIFICANCE Cancer is a severe threat to human health. Ferroptosis-based cancer therapy strategies are promising, but how to effectively induce ferroptosis in cancer cells in vivo is still a question without clear answers. Thus, the viewpoints raised in this review may provide some references and different perspectives for researchers working on ferroptosis-based cancer therapy.

中文翻译：

---

直接靶向谷胱甘肽过氧化物酶4可能比在基于肥大病的癌症治疗中破坏谷胱甘肽更有效。

背景技术癌症是对人类健康的主要威胁之一，并且目前的癌症疗法在根除癌症方面一直没有成功。Ferroptosis的特征是铁依赖性和脂质过氧化氢积累，其主要机制涉及抑制系统Xc-GSH（谷胱甘肽）-GPX4（谷胱甘肽过氧化物酶4）轴。碰巧的是，癌细胞在代谢上也具有铁成瘾和ROS耐受性的特征，这使其易患铁锈病。这可能为癌症治疗提供新的策略。综述的范围描述了肥大症的一般特征和机制，以及使癌细胞易患肥大症的基础。此外，我们着重讨论了破坏GSH可能不是触发体内癌细胞肥大化的理想方法，但直接抑制GPX4及其补偿成员可能更有效。最后，描述了直接抑制GPX4而又不干扰GSH的各种方法。主要结论靶向系统Xc-或GSH可能无法在体内通过其他补偿性途径有效触发癌细胞的肥大病。但是，直接靶向GPX4及其补偿成员而不破坏GSH可能更有效地在体内诱导癌细胞中的肥大症，因为GPX4对于预防肥大症至关重要。一般意义癌症是对人类健康的严重威胁。基于ferroptosis的癌症治疗策略是有前途的，但如何在体内有效诱导fertroptosis仍然是一个没有明确答案的问题。从而，