Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options.
基于严格调控铁细胞稳态的多层面分子机制，本综述深入探讨了其在生物系统中矛盾且潜在危险的作用，尤其聚焦于其与癌症相关的双刃剑效应。铁作为一种必需的微量营养素和多种关键细胞功能所需的辅因子，其诱发氧化应激的倾向既与癌症风险相关，也与癌细胞死亡通路的激活存在关联。在此背景下，铁死亡被定义为一种铁依赖性的调节性细胞死亡形式，其特征是由具有特定氧化磷脂谱的致死性过氧化物过量积累所驱动。作为一种独特的细胞死亡途径，铁死亡在形态学和机制上均不同于涉及执行蛋白家族的其他程序性细胞死亡类型。细胞毒性脂质过氧化物的积累体现了铁死亡执行系统与防御系统之间的细胞拮抗作用，当促铁死亡活性显著超过细胞抗氧化防御能力时，铁依赖性死亡随之发生。铁死亡执行机制的最新分子突破已引起肿瘤生物学界的高度关注，因为靶向铁死亡可为探索肿瘤抑制治疗策略提供新工具。基因突变与死亡/生存通路改变，以及癌细胞特有的代谢调控（包括活性氧生成倾向），均被视为可能使癌细胞对铁死亡失去保护的特征，从而暴露出值得进一步关注的脆弱性——这对于治疗选择有限的癌症而言，可能成为具有靶向潜力的突破口。
肿瘤(癌症)患者之家