Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
Exp Cell Res. 2024 Oct 1;442(2):114272. doi: 10.1016/j.yexcr.2024.114272.
The newly discovered programmed iron-dependent necrosis, ferroptosis, is a novel pathway that is controlled by iron-dependent lipid peroxidation and cellular redox changes. It can be triggered intrinsically by low antioxidant enzyme activity or extrinsically by blocking amino acid transporters or activating iron transporters. The induction of ferroptosis involves the activation of specific proteins, suppression of transporters, and increased endoplasmic reticulum (ER) stress (a condition in which the ER, a crucial organelle involved in protein folding and processing, becomes overwhelmed by an accumulation of misfolded or unfolded proteins. This situation disrupts the normal functioning of the ER, leading to a cellular stress response known as the unfolded protein response), leading to lipid peroxidation byproduct accumulation and toxic reactive oxygen species (ROS), which are highly reactive molecules derived from diatomic oxygen and include various forms such as superoxide (O₂⁻), hydroxyl radicals (•OH), and hydrogen peroxide (H₂O₂). Ferroptosis is closely associated with signaling molecules in lung cancer, including epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1-alpha (HIF-1α), and P53, and is regulated by epigenetic factors such as microRNAs (miRNAs). miRNAs are small non-coding RNA molecules that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Several miRNAs have been found to modulate ferroptosis by targeting key genes involved in iron metabolism, lipid peroxidation, and antioxidant defense pathways. The research on ferroptosis has expanded to target its role in lung cancer treatment and resistance prevention. This review encapsulates the significance of ferroptosis in lung cancer. Understanding the mechanisms and implications of ferroptosis in lung cancer cells may lead to targeted therapies exploiting cancer cell vulnerabilities to ferroptosis Also, improving treatment outcomes, and overcoming resistance.
新发现的程序性铁依赖性细胞坏死，即铁死亡，是一种受铁依赖性脂质过氧化和细胞氧化还原变化控制的新途径。它可以通过抗氧化酶活性低的内在因素或通过阻断氨基酸转运体或激活铁转运体的外在因素触发。铁死亡的诱导涉及到特定蛋白的激活、转运体的抑制和内质网（ER）应激的增加（内质网是一种参与蛋白质折叠和加工的关键细胞器，如果积累了错误折叠或未折叠的蛋白质，就会使其不堪重负。这种情况会破坏内质网的正常功能，导致一种称为未折叠蛋白反应的细胞应激反应），导致脂质过氧化产物积累和有毒的活性氧（ROS），ROS 是由双原子氧衍生而来的高度反应性分子，包括超氧化物（O₂⁻）、羟基自由基（•OH）和过氧化氢（H₂O₂）等多种形式。铁死亡与肺癌中的信号分子密切相关，包括表皮生长因子受体（EGFR）、丝裂原活化蛋白激酶（MAPK）、缺氧诱导因子 1-α（HIF-1α）和 P53，并且受表观遗传因素（如 microRNAs（miRNAs））的调节。miRNAs 是一种小的非编码 RNA 分子，通过与靶信使 RNA（mRNA）结合来调节基因表达，导致翻译抑制或降解。已经发现几种 miRNAs 通过靶向涉及铁代谢、脂质过氧化和抗氧化防御途径的关键基因来调节铁死亡。铁死亡的研究已经扩展到针对其在肺癌治疗和耐药预防中的作用。这篇综述总结了铁死亡在肺癌中的重要性。了解铁死亡在肺癌细胞中的机制和影响可能会导致利用癌细胞对铁死亡的脆弱性的靶向治疗，还可能改善治疗效果并克服耐药性。
