The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

自 2012 年提出该术语以来，铁死亡的研究领域在过去几年中呈指数级增长。这种由铁依赖性磷脂过氧化驱动的独特细胞死亡方式受到多种细胞代谢途径的调节，包括氧化还原稳态，铁处理、线粒体活性和氨基酸、脂质和糖的代谢，以及与疾病相关的各种信号通路。许多器官损伤和退行性病变是由铁死亡驱动的。有趣的是，抗治疗的癌细胞，特别是那些处于间充质状态且易于转移的癌细胞，非常容易受到铁死亡的影响。因此，通过诱导和抑制铁死亡的药理学调节，在治疗耐药性癌症方面具有巨大潜力，缺血性器官损伤和其他与广泛的脂质过氧化有关的退行性疾病。在这篇综述中，我们对铁死亡的当前分子机制和调控网络、铁死亡在肿瘤抑制和免疫监视中的潜在生理功能、病理作用以及治疗靶向的潜力进行了批判性分析。重要的是，与所有快速发展的研究领域一样，由于误解和不适当的实验方法，存在挑战。本综述还旨在解决这些问题，并为提高铁死亡研究的可重复性和可靠性提供实用指南。最后，我们讨论了应该成为未来铁死亡研究重点的重要概念和紧迫问题。