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Q1医学-3区,医学：内科-3区 2023 Apr 20; 136(8): 886–898.
8.15【预测↑】|7.19【实时↑】|6.1【2022最新】6.1
Q1医学-3区,医学：内科-3区 2023 Apr 20; 136(8): 886-898.
Ferroptosis in acute leukemia
急性白血病中的铁中毒
3监测编辑：高婷、郝秀娟
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Abstract 摘要
Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis, pyroptosis, and necrosis. The main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions, lipid peroxidation of cell membrane lipids, and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4 (GPX4). Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders, such as ischemia–reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply studied. This article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting ferroptosis. More importantly, it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.
铁凋亡是一种铁依赖性细胞死亡途径，不同于细胞凋亡、热凋亡和坏死。铁变态反应的主要特征是细胞内游离二价铁离子介导的芬顿反应、细胞膜脂质过氧化以及细胞内谷胱甘肽过氧化物酶 4（GPX4）抗脂质过氧化活性的抑制。最近的研究表明，铁氧化可参与多种疾病的病理过程，如缺血再灌注损伤、神经系统疾病和血液疾病。然而，铁蛋白沉积参与急性白血病发生和发展的具体机制仍有待更全面和深入的研究。本文综述了嗜铁细胞增多症的特点以及促进或抑制嗜铁细胞增多症的调控机制。更重要的是，文章进一步探讨了铁凋亡在急性白血病中的作用，并预测了铁凋亡在急性白血病中作用的进一步认识所带来的治疗策略的改变。
关键词急性淋巴细胞白血病 急性髓性白血病 铁氧化 氧化损伤 抗氧化防御 脂质过氧化物
Introduction 导言
The concept of ferroptosis, which is defined as iron-dependent regulated cell death, was put forward in 2012, and the main causes of ferroptosis are lipid peroxidation and plasma membrane rupture.[1–3] Ferroptosis is different from the common forms of regulated cell death previously discovered, such as apoptosis, pyroptosis, and necroptosis.[4] Apoptosis is mediated by molecules such as caspases 3/6/7/8/9, poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), B-cell lymphoma-2 (BCL2), BCL2 associated X (BAX), and BCL2 antagonist/killer 1 (BAK1). Pyroptosis also depends on the role of caspases, of which caspases 1/4/5/11 play a major role. In addition, pyroptosis is also regulated by gasdermin D (GSDMD), interleukin-1 beta (IL-1B), and interleukin-18 (IL-18). Necroptosis does not depend on the function of caspases; instead, receptor-interacting protein kinase 1 (RIPK1), RIPK, and mixed lineage kinase domain-like protein (MLKL) mediate its effects.[2,5] Studies have found that dozens of key cytokines, mainly including nuclear receptor coactivator 4 (NCOA4), arachidonate 15-lipoxygenase (ALOX15), voltage-dependent anion-selective channel protein 2 (VDAC2/3), solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member 2 (SLC3A2), glutathione peroxidase 4 (GPX4), transferrin receptor (TFR), transferrin (TF), and ferritin, are involved in the regulation of ferroptosis.
铁变性的概念是在2012年提出的，它被定义为铁依赖性调控细胞死亡，铁变性的主要原因是脂质过氧化和质膜破裂。 [1–3] 铁凋亡不同于之前发现的常见细胞调控死亡形式，如细胞凋亡、热凋亡和坏死。 [4] 细胞凋亡由 Caspases 3/6/7/8/9、多聚（腺苷二磷酸 [ADP]-核糖）聚合酶（PARP）、B 细胞淋巴瘤-2（BCL2）、BCL2 相关 X（BAX）和 BCL2 拮抗剂/杀手 1（BAK1）等分子介导。裂解也依赖于 Caspases 的作用，其中 Caspases 1/4/5/11起着主要作用。此外，化脓作用还受气体蛋白 D（GSDMD）、白细胞介素-1β（IL-1B）和白细胞介素-18（IL-18）的调控。坏死并不依赖于 Caspases 的功能，而是由受体相互作用蛋白激酶 1（RIPK1）、RIPK 和混合系激酶结构域样蛋白（MLKL）介导其作用。 [2,5] Studies have found that dozens of key cytokines, mainly including nuclear receptor coactivator 4 (NCOA4), arachidonate 15-lipoxygenase (ALOX15), voltage-dependent anion-selective channel protein 2 (VDAC2/3),溶质运载家族 7 成员 11 (SLC7A11)、溶质运载家族 3 成员 2 (SLC3A2)、谷胱甘肽过氧化物酶 4 (GPX4)、转铁蛋白受体 (TFR)、转铁蛋白 (TF) 和铁蛋白都参与了铁氧化的调控。
The main characteristics of ferroptosis are iron accumulation and excessive lipid peroxidation.[1,6,7] In recent years, there have been an increasing number of in-depth studies on the mechanism of ferroptosis. The system Xc- cystine/glutamate antiporter and GPX4 have been found to be involved in ferroptosis, and using the compounds erastin and an inhibitor of GPX4 (RSL3), respectively, to inhibit these two molecules can induce ferroptosis.[1,8–10] Uncontrolled lipid peroxidation is a sign of ferroptosis. Some studies have found that acyl-coenzyme A (acyl-CoA) synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are important factors driving ferroptosis.[11–13] Furthermore, certain lipoxygenases (LOX) can directly oxidize polyunsaturated fatty acids (PUFAs) on biofilms and thus are also considered to have a great potential to mediate ferroptosis.[14] An increasing number of studies have revealed the regulatory mechanism of ferroptosis, providing a sufficient theoretical basis for ferroptosis to be used to enhance treatment strategies in the future.
铁中毒的主要特征是铁积累和脂质过氧化。 [1,6,7] 近年来，关于铁中毒机制的深入研究越来越多。研究发现，Xc - 胱氨酸/谷氨酸拮抗剂系统和 GPX4 参与了铁变态反应，分别使用厄拉斯汀（erastin）和 GPX4 抑制剂（RSL3）抑制这两种分子可诱导铁变态反应。 [1,8–10] 不受控制的脂质过氧化是铁变态反应的一个标志。一些研究发现，酰基辅酶 A（酰基-CoA）合成酶长链家族成员 4（ACSL4）和溶血磷脂酰胆碱酰基转移酶 3（LPCAT3）是驱动铁变态反应的重要因素。 [11–13] 此外，某些脂氧化酶（LOX）可直接氧化生物膜上的多不饱和脂肪酸（PUFA），因此也被认为具有介导铁跃迁的巨大潜力。 [14] 越来越多的研究揭示了铁跃迁的调控机制，为今后利用铁跃迁加强治疗策略提供了充分的理论依据。
Leukemia is a group of heterogeneous hematopoietic stem cell (HSC) malignant tumors. Leukemic cells are abnormally aggregated and undifferentiated primordial cells, which can proliferate unrestrictedly in the bone marrow and interfere with the production of normal blood cells. Leukemia can be divided into acute and chronic leukemia.Acute leukemia (AL) contains acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). For now, there are many ways to treat leukemia clinically, but because of drug resistance or relapse, leukemia patients still need more treatment strategies.[15–18] A number of experiments and epidemiological studies have shown that iron metabolism disorders are related to the occurrence and development of AL.[19–21] The occurrence of leukemia involves many genes related to iron metabolism, including hemochromatosis (HFE) gene, transferrin receptor 1 gene, and other genes involved in iron metabolism. Leukemic cells showed an increase in iron uptake and a decrease in iron efflux, resulting in an increase in cellular iron levels.[7,22]
白血病是一组异质性造血干细胞恶性肿瘤。白血病细胞是异常聚集和未分化的原始细胞，可在骨髓中无限制地增殖，干扰正常血细胞的生成。白血病可分为急性白血病和慢性白血病。急性白血病（AL）包括急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）。目前，临床上治疗白血病的方法很多，但由于耐药或复发，白血病患者仍需要更多的治疗策略。 [15–18] 大量实验和流行病学研究表明，铁代谢紊乱与AL的发生和发展有关。 [19–21] 白血病的发生涉及许多与铁代谢有关的基因，包括血色素沉着病（HFE）基因、转铁蛋白受体 1 基因和其他参与铁代谢的基因。白血病细胞对铁的吸收增加，铁的外流减少，导致细胞铁含量增加。 [7,22]
At present, the main methods for the clinical treatment of leukemia are chemotherapy and bone marrow transplantation.[23,24] However, traditional chemotherapy drugs not only kill leukemia cells but also cause damage to healthy cells, causing huge side effects, and bone marrow transplantation is not suitable for all leukemia patients for various reasons. Although the development of chimeric antigen receptor (CAR)-T therapy provides a new hope for the treatment of leukemia, it is still not widely used because of its high price, troublesome preparation, and other limitations.[25] Leukemic cells are more easily affected by iron depletion than normal cells. Therefore, targeting the iron metabolic pathway may provide a good strategy for the treatment of AL. Ferroptosis is a newly discovered way of cell death. The rational use of ferroptosis will provide a new dawn for the treatment of AL.[26]
目前，临床治疗白血病的主要方法是化疗和骨髓移植。 [23,24] 然而，传统的化疗药物不仅会杀死白血病细胞，还会对健康细胞造成损伤，产生巨大的副作用，而骨髓移植由于种种原因也并不适合所有白血病患者。嵌合抗原受体（CAR）-T疗法的发展虽然为白血病的治疗带来了新的希望，但由于其价格昂贵、制备麻烦等局限性，目前仍未得到广泛应用。 [25] 与正常细胞相比，白血病细胞更容易受到铁耗竭的影响。因此，靶向铁代谢途径可能是治疗 AL 的良策。铁代谢是一种新发现的细胞死亡方式。合理利用铁代谢将为 AL 的治疗带来新的曙光。 [26]
History of Ferroptosis 铁中毒症的历史
As early as 1980, it was found that system Xc- could transport cystine into cells in exchange for glutamate.[27] It has been reported that inhibition of cystine transport can induce glutamate toxicity in nerve cells and produce oxidative stress.[28] In 1997, studies showed that inhibition of arachidonate 12-lipoxygenase (Alox12) could inhibit glutamate-induced cell death in the hippocampal cell line HT22 and primary cortical neurons.[29] In 2003, erastin, an inducer of ferroptosis, was discovered in high-throughput small-molecule screening studies. Erastin have lethal effects on rat sarcoma (RAS)-mutant tumor cells.[30] In 2012, the concept of ferroptosis was formally proposed, and studies have found that erastin induces cell death by inhibiting cystine uptake via system Xc-.[1] Soon after in 2014, another important molecule related to ferroptosis, GPX4, was discovered. Yang et al[8] reported that GPX4 can prevent ferroptosis by reducing phospholipid hydrogen peroxide, thereby inhibiting LOX-mediated lipid peroxidation. Two years later, it was reported that PUFA oxidation by LOX triggers ferroptosis.[31] In 2017, studies showed that ACSL4 is a biomarker of and plays a key role in ferroptosis and is necessary to produce the PUFAs needed for ferroptosis.[12] In 2018, a study of GPX4 showed that selenium was necessary for GPX4 to inhibit ferroptosis.[32] Recently, studies have shown that the coenzyme Q10 (CoQ10) reductase ferroptosis suppressor protein 1 (FSP1) can inhibit ferroptosis in a glutathione (GSH)-independent manner, providing a new pathway for the study of ferroptosis.[33,34] In a 2020 study to identify ferroptosis-sensitive genes, we found that oxidizing organelle peroxisomes can increase ferroptosis sensitivity through the synthesis of polyunsaturated fatty ether phospholipids.[35] With more in-depth research, it has been found that there is a strong relationship between ferroptosis and the immune system. Follicular helper T (Tfh) cells are a specialized subset of cluster of differentiation 4 (CD4) T cells that essentially support germinal center responses generating high-affinity and long-lived humoral immunity. The regulation of T cell survival remains unclear. Kuhn's findings reveal the central role of the selenium–GPX4–ferroptosis axis in regulating Tfh homeostasis, which can be targeted to enhance T cells' function in infection and following vaccination [Figure [Figure11].
早在 1980 年，人们就发现 Xc 系统 - 可以将胱氨酸转运到细胞中，以交换谷氨酸。 [27] 据报道，抑制胱氨酸转运可诱发神经细胞谷氨酸中毒，并产生氧化应激。 [28] 1997 年，研究表明，抑制花生四烯酸 12-脂氧合酶（Alox12）可抑制谷氨酸诱导的海马细胞系 HT22 和初级皮质神经元的细胞死亡。 [29] 2003 年，在高通量小分子筛选研究中发现了一种铁变态反应诱导剂--依拉斯汀。厄拉斯特素对大鼠肉瘤（RAS）突变肿瘤细胞具有致死作用。 [30] 2012 年，"铁跃迁 "的概念被正式提出，研究发现厄拉斯汀通过 Xc 系统抑制胱氨酸的吸收诱导细胞死亡 - 。 [1] 不久后的2014年，另一个与铁跃迁有关的重要分子--GPX4被发现。Yang等人 [8] ，报道了GPX4可通过减少磷脂过氧化氢从而抑制LOX介导的脂质过氧化作用来防止铁变态反应。两年后，有报道称LOX氧化PUFA会引发铁变态反应。 [31] 2017 年，研究表明 ACSL4 是铁变态反应的生物标志物，并在铁变态反应中发挥关键作用，是产生铁变态反应所需的 PUFA 的必要条件。 [12] 2018年，一项关于GPX4的研究表明，硒是GPX4抑制铁变态反应的必要条件。 [32] 最近的研究表明，辅酶Q10（CoQ10）还原酶铁氧化抑制蛋白1（FSP1）可以不依赖谷胱甘肽（GSH）的方式抑制铁氧化，为铁氧化的研究提供了新的途径。 [33,34] 2020 年，我们在一项鉴定铁变态反应敏感基因的研究中发现，氧化细胞器过氧物酶体可以通过合成多不饱和脂肪醚磷脂来提高铁变态反应的敏感性。 [35] 随着研究的深入，我们发现铁变态反应与免疫系统之间有着密切的关系。滤泡辅助 T 细胞（Tfh）是分化 4 簇（CD4）T 细胞的一个特化亚群，主要支持生殖中心反应，产生高亲和力和长效体液免疫。T细胞存活的调控机制仍不清楚。库恩的研究结果揭示了硒-GPX4-铁突变轴在调节Tfh稳态中的核心作用，可以通过调节硒-GPX4-铁突变轴来增强T细胞在感染和接种疫苗后的功能[图11]。
Timeline of the discovery of important molecules related to ferroptosis. Based on the findings of a large number of basic studies, the formal definition of "ferroptosis" was proposed in 2012. Since then, many studies have revealed the important molecules and mechanisms related to ferroptosis. ACSL4: Acyl-CoA synthetase long-chain family member 4; AlOX12: Arachidonate 12-lipoxygenase; FSP1: Ferroptosis suppressor protein 1; GPX4: Glutathione peroxidase 4; PUFA: Polyunsaturated fatty acid.
与铁中毒症有关的重要分子的发现时间表。基于大量基础研究的发现，2012 年提出了 "铁变态反应 "的正式定义。从那时起，许多研究揭示了与铁变态反应相关的重要分子和机制。ACSL4：酰基-CoA 合成酶长链家族成员 4；AlOX12：花生四烯酸 12-脂氧合酶；FSP1：铁变态反应抑制蛋白 1；GPX4：谷胱甘肽过氧化物酶 4；PUFA：多不饱和脂肪酸。
Characteristics of Ferroptosis
铁中毒的特征
Ferroptosis is different from other forms of regulated cell death, such as apoptosis, pyroptosis, and necroptosis, in terms of morphological characteristics, biochemical immune characteristics, and genetic regulation. Ferroptosis is characterized by the following morphological features: (1) a significantly decreased mitochondrial crest, increased membrane density, and rupture of the membrane, leading to atrophy of mitochondria; (2) a normal nucleus; and (3) increased cell membrane density and a disintegrated cell membrane. Ferroptosis is characterized by the following biochemical and immune characteristics: (1) apparently decreased mitochondrial membrane potential; (2) significantly increased intracellular iron ion level; (3) markedly increased reactive oxygen species (ROS) level; (4) enhanced lipid peroxidation; (5) release of injury-related molecular factors that promote the inflammatory response; and (6) caspase independence.[1,5,36–38]
铁凋亡与细胞凋亡、热凋亡和坏死等其他调节性细胞死亡形式在形态特征、生化免疫特征和遗传调控方面都有所不同。铁凋亡具有以下形态特征：(1）线粒体嵴明显减少，膜密度增加，膜破裂，导致线粒体萎缩；（2）细胞核正常；（3）细胞膜密度增加，细胞膜解体。铁中毒具有以下生化和免疫特征：(1) 线粒体膜电位明显降低；(2) 细胞内铁离子水平显著升高；(3) 活性氧（ROS）水平明显升高；(4) 脂质过氧化反应增强；(5) 释放促进炎症反应的损伤相关分子因子；(6) 独立于 Caspase。 [1,5,36–38]
Mechanism of Ferroptosis 铁蛋白沉积机制
The main features of ferroptosis are increased iron and the accumulation of lipid peroxides on the membrane.[2] The core function of ferroptosis is to balance oxidative damage and antioxidant defense[3,39] [Figure [Figure22].
铁变态反应的主要特征是铁的增加和膜上脂质过氧化物的积累。 [2] 铁变态反应的核心功能是平衡氧化损伤和抗氧化防御 [3,39] [图[图22]。
The function of the ferroptosis mechanism is to balance oxidative damage and antioxidant defense. The mechanism of ferroptosis mainly involves two parts: oxidative damage and antioxidant defense. When the physiological state of the body changes and oxidative damage increases, ferroptosis and ferroptotic cell death are induced; in contrast, overexuberant antioxidant defense hinders the occurrence of ferroptosis. AA: Arachidonic acid; ACSL4: Acyl-CoA synthetase long-chain family member 4; AdA: Adrenic acid; BH4: Tetrahydrobiopterin; CoQ10: Coenzyme Q10; CoQ12: Coenzyme Q12; FSP1: Ferroptosis suppressor protein 1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; iNOS: Inducible nitric oxide synthase; LOX: Lipoxygenase; NCOA4: Nuclear receptor coactivator 4; NO: Nitric oxide; NRF2: Nuclear factor erythroid 2-related factor 2; PE-AA: Arachidonic acid-phosphatidylethanolamine; PLOOHs: Phospholipid hydroperoxides; PUFA: Polyunsaturated fatty acid; ROS: Reactive oxygen species; SLC3A2: Solute carrier family 3 member 2; TF: Transferrin.
铁氧化机制的功能是平衡氧化损伤和抗氧化防御。铁氧化机制主要包括氧化损伤和抗氧化防御两部分。当机体的生理状态发生变化，氧化损伤加重时，就会诱发铁变态反应和铁变态细胞死亡；相反，过度的抗氧化防御则会阻碍铁变态反应的发生。AA：花生四烯酸；ACSL4：酰基-CoA 合成酶长链家族成员 4；AdA：肾上腺酸；BH4：四氢生物蝶呤；CoQ10：辅酶 Q10；CoQ12：辅酶 Q12：FSP1：铁突变抑制蛋白 1；GPX4：谷胱甘肽过氧化物酶 4；GSH：谷胱甘肽；iNOS：诱导型一氧化氮合酶；LOX：脂氧合酶；NCOA4：核受体辅激活因子 4；NO：一氧化氮；NRF2：核因子红细胞 2 相关因子 2；PE-AA：花生四烯酸-磷脂酰乙醇胺；PLOOHs：磷脂氢过氧化物；PUFA：多不饱和脂肪酸；ROS：活性氧：SLC3A2：溶质运载家族 3 成员 2；TF：转铁蛋白。
Oxidative damage 氧化损伤
Lipid peroxidation
Lipid peroxidation refers to the loss of hydrogen atoms by lipids under the action of free radicals or lipid peroxidases, which leads to the oxidation, breaking, and shortening of lipid carbon chains and the production of cytotoxic substances such as lipid free radicals, lipid hydroperoxides, and active aldehydes, resulting in cell damage.[40] PUFAs, an important component of the cell membrane, are the main substrate of lipid peroxidation during ferroptosis. PUFAs are long-chain fatty acids with more than two double bonds that regulate many important physiological activities, such as growth, proliferation, differentiation, senescence, immunity, and inflammation. PUFAs are easily oxidized, and the more double bonds they contain, the higher their oxidation sensitivity.[41–46] Some studies have shown that ROS mainly attacks PUFAs located on the cell membrane. Lipid peroxidation of PUFAs begins with the formation of lipid free radicals. Subsequently, lipid free radicals interact with oxygen molecules to form lipid peroxidation free radicals. Lipid peroxidation free radicals can continuously participate in the oxidation of PUFAs; as such, the lipid peroxidation of PUFAs occurs via a cascade reaction. The PUFAs that participate in the induction of ferroptosis are mainly arachidonic acid (AA) and adrenic acid (AdA).[47] Furthermore, ACSL4 and lysophosphatidylcholine acyltransferase 3 (LPCAT3) also play an important role in this process. It has been reported that reducing ACSL4 can reduce the sensitivity of cells to iron-related death, while upregulation of ACSL4 expression after inhibition of the nuclear factor E2-related factor 2 (NRF2)-yes1 associated transcriptional regulator (YAP) pathway can promote ferroptosis.[48–50] LPCAT3 targets acetylated AA and esterifies CoA-AA intermediates to form arachidonic acid-phosphatidylethanolamine PE-AA, which ultimately leads to ferroptosis under the action of LOX.[13,46,51] In recent years, because LOX can oxidize PUFAs located on the cell membrane, researchers have begun to explore whether LOX can mediate ferroptosis.[14] It has been reported that ferroptosis induced by 12-LOX can promote the inhibition of p53-dependent tumors.[52] The application of LOX inhibitors can inhibit ferroptosis.[29,53] However, since more experimental evidence is needed to determine whether LOX is directly related to ferroptosis, we cannot conclude that LOX can mediate ferroptosis.
脂质过氧化 脂质过氧化是指脂质在自由基或脂质过氧化物酶的作用下失去氢原子，导致脂质碳链氧化、断裂和缩短，产生脂质自由基、脂质氢过氧化物和活性醛等细胞毒性物质，造成细胞损伤。 [40] PUFA 是细胞膜的重要组成部分，是铁变态反应过程中脂质过氧化反应的主要底物。PUFA 是具有两个以上双键的长链脂肪酸，可调节许多重要的生理活动，如生长、增殖、分化、衰老、免疫和炎症。PUFAs 易于氧化，双键越多，氧化敏感性越高。 [41–46] 一些研究表明，ROS 主要攻击位于细胞膜上的 PUFA。PUFA 的脂质过氧化首先会形成脂质自由基。随后，脂质自由基与氧分子相互作用，形成脂质过氧化自由基。脂质过氧化自由基可持续参与 PUFAs 的氧化；因此，PUFAs 的脂质过氧化是通过级联反应发生的。参与诱导铁变态反应的 PUFAs 主要是花生四烯酸（AA）和肾上腺酸（AdA）。 [47] 此外，ACSL4 和溶血磷脂酰胆碱酰基转移酶 3（LPCAT3）也在这一过程中发挥重要作用。据报道，减少 ACSL4 可降低细胞对铁相关死亡的敏感性，而抑制核因子 E2 相关因子 2（NRF2）-Yes1 相关转录调节因子（YAP）通路后上调 ACSL4 的表达可促进铁变态反应。 [48–50] LPCAT3靶向乙酰化AA，酯化CoA-AA中间产物形成花生四烯酸-磷脂酰乙醇胺PE-AA，在LOX的作用下最终导致铁凋亡。 [13,46,51] 近年来，由于 LOX 可以氧化位于细胞膜上的 PUFAs，研究人员开始探索 LOX 是否可以介导铁凋亡。 [14] 有报道称，12-LOX 诱导的铁跃迁可促进抑制 p53 依赖性肿瘤。 [52] 应用 LOX 抑制剂可以抑制铁跃迁。 [29,53] 然而，由于还需要更多的实验证据来确定 LOX 是否与铁跃迁直接相关，我们还不能得出 LOX 可以介导铁跃迁的结论。
Role of iron 铁的作用
Iron is a necessary nutrient for living creatures. The level of iron in cells is a result of the balance between the absorption, output, utilization, and storage of iron. When ferroptosis occurs, a large amount of free divalent Fe2+ accumulates in cells, which mainly comes from the binding of TF with Fe3+ to TFR on the plasma membrane. TF enters the cell, and Fe3+ dissociates from TF and is reduced to Fe2+ or combines with ferritin to be stored in the iron pool. Additionally, ferritin in the iron pool can be degraded, which releases a large amount of divalent iron ions, in a process mediated by nuclear receptor coactivator 4 (NCOA4), serving as another source of free Fe2+.[54–56] Current studies suggest that excess iron can promote lipid peroxidation and then induce ferroptosis by two main mechanisms, namely, the generation of ROS via the iron-dependent Fenton reaction and the activation of iron-containing enzymes (e.g., LOX).[2,57] In the Fenton reaction, extremely oxidative free Fe2+ easily reacts with H2O2 to produce hydroxyl radicals that can cause oxidative damage to deoxyribonucleic acid (DNA), proteins, and membrane lipids, promoting lipid peroxidation, damaging the cell membrane, and eventually leading to cell death. Fenton's reaction formula is Fe2+ + H2O2 → Fe3+ + (OH)－ + OH·.[38] In addition, studies have shown that the enzymes LOX and nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase (POR), which are related to phospholipid peroxidation, require iron catalysis to participate in ferroptosis.[10,58]
铁是生物所必需的营养物质。细胞中铁的含量是铁的吸收、输出、利用和储存之间平衡的结果。当发生铁变态反应时，细胞中会积聚大量游离的二价铁 2+ ，这主要来自质膜上的 TF 与铁 3+ 与 TFR 的结合。TF 进入细胞，Fe 3+ 与 TF 解离，还原为 Fe 2+ 或与铁蛋白结合储存在铁池中。此外，铁池中的铁蛋白可被降解，从而释放出大量二价铁离子，这一过程由核受体辅激活因子 4（NCOA4）介导，是游离铁的另一个来源 2+ 。 [54–56] 目前的研究表明，过量铁能促进脂质过氧化，然后通过两种主要机制诱导铁变态反应，即通过铁依赖的芬顿反应产生 ROS 和激活含铁酶（如 LOX）。 [2,57] 在芬顿反应中，极易氧化的游离铁 2+ 很容易与 H 2 O 2 反应生成羟自由基，从而对脱氧核糖核酸（DNA）、蛋白质和膜脂造成氧化损伤，促进脂质过氧化，破坏细胞膜，最终导致细胞死亡。芬顿反应式为：Fe 2+ + H 2 O 2 → Fe 3+ + (OH) － + OH-。 [38] 此外，研究表明，与磷脂过氧化有关的 LOX 和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）-细胞色素 P450 还原酶（POR）需要铁催化才能参与铁变态反应。 [10,58]
Antioxidant defense 抗氧化防御
GPX4-dependent pathway
GPX4 is a selenium-containing cysteine and GSH-dependent enzyme belonging to the GSH peroxidase family (including GPX1-8). It is a necessary enzyme that scavenges lipid hydrogen peroxide by reducing it to the corresponding ethanol or reducing H2O2 to free H2O2 and water. As such, GPX4 plays an important role in preventing ferroptosis.[59–61] In recent years, studies have shown that the cystine-importing GSH-GPX4 machinery plays an important role in the prevention of ferroptosis, and it has been proven that phospholipid hydroperoxide (PLOOH) is a substrate of GPX4 and might be an executor of ferroptosis.[62] GSH is synthesized by the catalysis of the cytosolic enzymes glutamate cysteine ligase (GCL) and glutathione synthetase (GSS) and participates in the regulation of ferroptosis.[63] GSH can produce glutathione disulfide (GSSG), and GSSG regenerates GSH through glutathione reductase (GR). In this process, GSH can act as an electron donor, so GSH is necessary for the GPX4 catalytic reaction and an important factor for maintaining the activity of GPX4. Because GSH participates in maintaining the activity of GPX4, GPX4 can prevent ferroptosis. In addition, cystine is the most restricted amino acid in the process of GSH synthesis, so the cystine-importing GSH-GPX4 machinery is the most critical signaling pathway for preventing ferroptosis. It has been reported that the cystine/glutamate antiporter system Xc- can promote ferroptosis by inhibiting cysteine import.[1,64,65] Additionally, erastin can inhibit cysteine input and inactivate GPX4 indirectly, resulting in the accumulation of PLOOH, a substrate of GPX4, and the accumulation of PLOOH can quickly initiate the Fenton reaction; in addition, the amount of PLOOH can be rapidly increased, resulting in ferroptotic cell death. Selenium is an essential element for organisms and participates in many important physiological processes in the body.[34] In addition to the cystine-importing GSH-GPX4 signaling pathway, selenium can also affect the expression of GPX4 and induce ferroptosis. It has been suggested that selenium can regulate GPX4 expression by increasing ribosome transfer RNA (tRNA) density downstream of UGA-Sec codons and selenium incorporation efficiency in part by affecting the degree of Sec-tRNA[Ser]SecUm34 methylation. Sec-tRNA must first be activated by the addition of an isopentenyl lipid group, a product of the mevalonate (MVA) pathway. This phenomenon may explain how disruption of the MVA pathway by statins leads to reduced GPX4 expression and increased ferroptosis in certain cells.[66–69]
GPX4 依赖性途径 GPX4 是一种含硒半胱氨酸和 GSH 依赖性酶，属于 GSH 过氧化物酶家族（包括 GPX1-8）。它是清除脂质过氧化氢的必要酶，可将过氧化氢还原成相应的乙醇或将 H 2 O 2 还原成游离的 H 2 O 2 和水。因此，GPX4 在防止铁变态反应方面发挥着重要作用。 [59–61] 近年来的研究表明，胱氨酸输入的 GSH-GPX4 机制在预防铁猝死中发挥着重要作用，而且磷脂过氧化氢（PLOOH）是 GPX4 的底物，可能是铁猝死的执行者。 [62] GSH 在细胞膜酶谷氨酸半胱氨酸连接酶（GCL）和谷胱甘肽合成酶（GSS）的催化下合成，并参与调节铁变态反应。 [63] GSH 可产生二硫化谷胱甘肽（GSSG），而 GSSG 可通过谷胱甘肽还原酶（GR）再生 GSH。在这一过程中，GSH 可充当电子供体，因此 GSH 是 GPX4 催化反应所必需的，也是维持 GPX4 活性的重要因素。由于 GSH 参与维持 GPX4 的活性，因此 GPX4 可以防止铁蜕变。此外，胱氨酸是 GSH 合成过程中最受限制的氨基酸，因此胱氨酸输入 GSH-GPX4 机制是防止铁猝灭的最关键信号通路。据报道，胱氨酸/谷氨酸拮抗剂系统 Xc - 可通过抑制半胱氨酸的输入来促进铁变态反应。 [1,64,65] 此外，麦拉宁可抑制半胱氨酸输入，间接使 GPX4 失活，导致 GPX4 的底物 PLOOH 积累，PLOOH 的积累可迅速引发 Fenton 反应；此外，PLOOH 的量可迅速增加，导致铁猝死细胞死亡。硒是生物体的必需元素，参与体内许多重要的生理过程。 [34] 除了胱氨酸输入的 GSH-GPX4 信号通路外，硒还能影响 GPX4 的表达并诱导铁变态反应。有研究认为，硒可以通过增加 UGA-Sec 密码子下游的核糖体转运 RNA（tRNA）密度和硒结合效率来调节 GPX4 的表达，部分原因是硒影响了 Sec-tRNA[Ser]SecUm34 甲基化的程度。Sec-tRNA 必须首先通过添加异戊烯基脂基（甲羟戊酸（MVA）途径的产物）来激活。这一现象可以解释他汀类药物为何会破坏 MVA 途径，从而导致某些细胞中 GPX4 表达减少和铁变态反应增加。 [66–69]
GPX4-independent pathway
To date, the most important signaling axis known to regulate ferroptosis is dependent on GPX4. Inhibition of GPX4 to induce ferroptosis is a new therapeutic strategy for the treatment of tumors. However, different cell lines have different sensitivities to GPX4 inhibitors. Therefore, we speculate that there are other mechanisms regulating ferroptosis in the body that do not depend on GPX4.[11] Through CRISPR/cas9 screening, Doll et al[33] found that FSP1 is an anti-ferroptosis gene.[34] Other studies on FSP1 have proven that FSP1 is a powerful ferroptosis inhibitor independent of GPX4, GSH, or ACSL4.[34] FSP1 was initially reported to be involved in p53-mediated apoptosis because its amino acid sequence is similar to that of human apoptosis-inducing factor (AIF), so it is also called AIF-like mitochondrion-associated inducer of death (AMID).[70–72] Many studies have shown that FSP1 can regulate the ferroptosis sensitivity of cells. FSP1 is an oxidoreductase that can reduce CoQ10 to ubiquinol, which is a lipophilic free radical-trapping antioxidant that can prevent lipid peroxidation. Therefore, FSP1 inhibits ferroptosis through this process.[34]
独立于 GPX4 的途径 迄今为止，已知调控铁氧化酶的最重要信号轴依赖于 GPX4。抑制 GPX4 以诱导铁氧化是治疗肿瘤的一种新疗法。然而，不同细胞系对 GPX4 抑制剂的敏感性不同。因此，我们推测体内还有其他不依赖于 GPX4 的机制来调节铁氧化。 [11] 通过 CRISPR/cas9 筛选，Doll 等人 [33] 发现 FSP1 是一个抗铁蛋白沉积基因。 [34] 其他有关 FSP1 的研究证明，FSP1 是一种独立于 GPX4、GSH 或 ACSL4 的强大的铁突变抑制剂。 [34] FSP1 最初被报道参与 p53 介导的细胞凋亡，因为它的氨基酸序列与人类细胞凋亡诱导因子（AIF）相似，所以也被称为 AIF-like mitochondrion-associated inducer of death（AMID）。 [70–72] 许多研究表明，FSP1 可以调节细胞的铁凋亡敏感性。FSP1 是一种氧化还原酶，可将 CoQ10 还原成泛醌，泛醌是一种亲脂性捕获自由基的抗氧化剂，可防止脂质过氧化。因此，FSP1 可通过这一过程抑制铁突变。 [34]
The study of Chen et al[73] shows that the inhibition of ferroptosis by FSP1 is independent of GPX4, and the myristoylation of FSP1 mediates the recruitment of FSP1 to the cell membrane, which plays an important role in the inhibition of ferroptosis by FSP1. In addition to FSP1 and GPX4 playing an important role in the inhibition of ferroptosis, a large number of studies have shown that natural antioxidants such as vitamin E, thioredoxin, and mitoquinone can also participate in the inhibition of ferroptosis.[74–76] Recent research discovered that inducible nitric oxide synthase (iNOS)/NO∙ abundance modulates susceptibility to ferroptosis in macrophages/microglia.[77] The free radical-capturing antioxidant tetrahydrobiopterin (BH4) inhibits ferroptosis by reducing lipid peroxidation.[78] Furthermore, NRF2 can play an important role in ferroptosis through many different pathways.[79–85]
Chen 等人的研究 [73] 表明，FSP1 对铁跃迁的抑制作用与 GPX4 无关，FSP1 的肉豆蔻酰化介导 FSP1 募集到细胞膜上，在 FSP1 抑制铁跃迁的过程中发挥了重要作用。除了 FSP1 和 GPX4 在抑制铁跃迁中发挥重要作用外，大量研究表明，维生素 E、硫氧还蛋白和线粒体醌等天然抗氧化剂也能参与抑制铁跃迁。 [74–76] 最近的研究发现，诱导型一氧化氮合酶（iNOS）/NO∙的丰度可调节巨噬细胞/小胶质细胞对铁中毒的易感性。 [77] 捕获自由基的抗氧化剂四氢生物蝶呤（BH4）可通过减少脂质过氧化抑制铁中毒。 [78] 此外，NRF2 可通过多种不同途径在铁跃迁中发挥重要作用。 [79–85]
Abnormal Iron Metabolism and Leukemic Cells
铁代谢异常与白血病细胞
Cancer cells will change the normal mechanism of iron metabolism for proliferation, and abnormal iron metabolism is closely related to the occurrence and development of leukemia.[86] Patients with leukemia need a large number of red blood cell transfusions due to disturbance of erythropoiesis and anemia caused by chemotherapy, so iron overload often occurs. Abnormal iron metabolism will seriously affect normal hematopoiesis. The expression of TFR1 in leukemic cells is generally higher than that in normal controls, and its level may be directly related to the differentiation of AML.[87] However, iron depletion caused by TFR1 inhibition can damage the proliferation and differentiation of hematopoietic progenitor cells and reduce the regeneration potential of HSCs.[88] TFR2 is also upregulated in AML subtypes (AML1, AML2, and AML6). Some studies have shown that the expression of TFR2 α subtypes may be positively correlated with a good prognosis.[89–91] Excess iron and ROS catalytic products promote the malignant transformation of HSCs through nicotinamide adenine dinucleotide phosphate oxidase (NOX) and subsequent GSH depletion.[92] At the same time, ROS may also promote the transformation process of AML.[93] In monocyte AML, the increase of ROS can induce apoptosis of adjacent natural killer (NK) cells and CD4 and CD8 T cells through poly-ADP-ribose polymerase-1 (PARP1), and invalidate the subsequent anti-leukemia response.[94] Serum ferritin is also frequently increased in patients with leukemia and is associated with poor prognosis in patients undergoing chemotherapy[95–98] and patients receiving allogeneic stem cell transplantation.[99] In patients with AML, overexpression of ferritin heavy chain (FTH) leads to chemotherapy resistance through nuclear factor-kappa B (NF-κB) pathway and pro-oxidative pathway.[95] It is worth noting that the low expression of ferroportin in AML seems to be associated with improved prognosis and higher chemosensitivity.[100]
癌细胞为了增殖会改变铁代谢的正常机制，铁代谢异常与白血病的发生和发展密切相关。 [86] 白血病患者由于化疗引起的红细胞生成障碍和贫血，需要大量输注红细胞，因此常出现铁超载。铁代谢异常会严重影响正常的造血功能。白血病细胞中 TFR1 的表达通常高于正常对照组，其水平可能与 AML 的分化直接相关。 [87] 然而，抑制 TFR1 造成的铁耗竭会损害造血祖细胞的增殖和分化，降低造血干细胞的再生潜能。 [88] 在急性髓细胞性白血病亚型（AML1、AML2 和 AML6）中，TFR2 也会上调。一些研究表明，TFR2 α 亚型的表达可能与良好的预后呈正相关。 [89–91] 过量的铁和 ROS 催化产物通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）和随后的 GSH 消耗促进造血干细胞的恶性转化。 [92] 同时，ROS 还可能促进急性髓细胞性白血病的转化过程。 [93] 在单核细胞急性髓细胞白血病中，ROS 的增加可通过聚-ADP-核糖聚合酶-1（PARP1）诱导邻近的自然杀伤（NK）细胞、CD4 和 CD8 T 细胞凋亡，使随后的抗白血病反应失效。 [94] 血清铁蛋白在白血病患者中也经常升高，在接受化疗 [95–98] 和异基因干细胞移植的患者中与预后不良有关。 [99] 在急性髓细胞性白血病患者中，铁蛋白重链（FTH）的过度表达会通过核因子卡巴B（NF-κB）途径和促氧化途径导致化疗耐药。 [95] 值得注意的是，铁蛋白在急性髓细胞性白血病中的低表达似乎与预后改善和化疗敏感性增高有关。 [100]
Recent Advances of Ferroptosis in AL
AL 中铁蛋白沉积的最新进展
In recent years, studies related to ferroptosis have emerged, and many studies have shown that ferroptosis is closely related to the occurrence and development of tumors.[26,38,101–104] Here, we focus on AL and report that ferroptosis affects the occurrence and development of AL through various pathways, including various signaling pathways, natural extracts, drugs, compounds, ferroptosis-related molecules, and so on [Figure [Figure33 and Table Table11].
近年来，有关嗜铁细胞增多症的研究不断涌现，许多研究表明，嗜铁细胞增多症与肿瘤的发生和发展密切相关。 [26,38,101–104] 在此，我们以AL为研究对象，报道了嗜铁细胞通过各种途径影响AL的发生和发展，包括各种信号通路、天然提取物、药物、化合物、嗜铁细胞相关分子等[图33和表11]。
Summary of the mechanisms related to ferroptosis in AML and ALL cells. The interaction of various molecules forms a network of molecular pathways related to ferroptosis. In AML cells, the upregulation of p53 expression by circKDM4C via hsa-let-7b-5p can reduce ferroptosis; also, APR-246 can target the mutant protein p53 in AML and promote the binding of mutant p53 to the target site of DNA to regain its transcriptional activity, the combination of APR-246 with ferroptosis inducers, or the inactivation of SLC7A11 has synergistic anti-leukemic activity in vitro; HMGB1 can regulate Erastin-induced ferroptosis through Ras-JNK/p38 signal pathway; additionally, some drugs or natural abstracts can also induce ferroptosis and help to fight AML. In ALL cells, the ubiquitination of PAQR3 by NRF2 can induce ferroptosis; RSL3 can induce ferroptosis by enhancing the production of ROS and this process can be blocked by LOX inhibitors or ferroptosis inhibitors; HD induces ferroptosis via reducing GSH and GPX4. ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; AMPK: Adenosine monophosphate-activated protein kinase; APR-246: Eprenetapopt; ATLL: Adult T cell leukemia/lymphoma; ATPR: 4-Amino-2-trifluoromethyl-phenyl retinate; DFA: Deferoxamine; DHA: Dihydroartemisinin; DNA: Deoxyribonucleic acid; Fer-1: Ferrostain-1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HD: Hydnocarpin D; HMGB1: High mobility group protein 1; KDM4C: Lysine demethylase 4c; LOX: Lipoxygenases; NRF2: Nuclear factor erythroid 2-related factor 2; PAQR3: Progestin and adipoq receptor family member 3; Ras-JNK: Rat sarcoma-jun N-terminal kinase; ROS: Reactive oxygen species; RSL3: An inhibitor of glutathione peroxidase 4; SLC7A11: Solute carrier family 7 member 11; ub: Ubiquitination.
概述急性髓细胞性白血病和 ALL 细胞中与铁凋亡有关的机制。各种分子的相互作用形成了与铁凋亡相关的分子通路网络。在AML细胞中，circKDM4C通过hsa-let-7b-5p上调p53的表达可降低铁突变；同时，APR-246可靶向AML中的突变蛋白p53，促进突变p53与DNA靶位点结合，恢复其转录活性，APR-246与铁突变诱导剂联合使用，或使SLC7A11失活，在体外具有协同抗白血病活性；HMGB1可通过Ras-JNK/p38信号通路调控Erastin诱导的铁变态反应；此外，一些药物或天然提取物也可诱导铁变态反应，有助于抗击AML。在ALL细胞中，NRF2对PAQR3的泛素化可诱导铁嗜铬细胞增多；RSL3可通过增强ROS的产生诱导铁嗜铬细胞增多，这一过程可被LOX抑制剂或铁嗜铬细胞增多抑制剂阻断；HD可通过减少GSH和GPX4诱导铁嗜铬细胞增多。急性淋巴细胞白血病急性淋巴细胞白血病；AML：AMPK：单磷酸腺苷激活的蛋白激酶；APR-246：Eprenetapopt； ATLL：成人 T 细胞白血病/淋巴瘤； ATPR：4-氨基-2-三氟甲基苯基视黄酸酯； DFA：去铁胺； DHA：双氢青蒿素； DNA：脱氧核糖核酸：GPX4：谷胱甘肽过氧化物酶 4；GSH：谷胱甘肽；HD：水黄素 D；HMGB1：高迁移率基团蛋白 1；KDM4C：赖氨酸去甲基化酶 4c：LOX：脂氧合酶；NRF2：核因子红细胞 2 相关因子 2；PAQR3：PAQR3：孕激素和脂肪受体家族成员 3；Ras-JNK：大鼠肉瘤君 N 端激酶；ROS：RSL3：谷胱甘肽过氧化物酶 4 抑制剂；SLC7A11：溶质运载家族 7 成员 11；ub：泛素化。
Table 1 表 1
Ferroptosis-related compounds, natural extracts, and drugs for acute leukemia and their mechanisms.
治疗急性白血病的铁突变相关化合物、天然提取物和药物及其机制。
|
Compound/drug/natural extract 化合物/药物/天然提取物 | Disease | Mechanism |
|---|---|---|
| APR-246 | AML | Deplete intracellular GSH and induce lipid peroxide production 消耗细胞内 GSH 并诱导产生过氧化脂质 |
| DHA | AML | Induce autophagy by regulating the activity of AMPK/mTOR/70 kDa ribosomal protein S6 kinase (p70S6K) signaling pathway, accelerate the degradation of ferritin, increase the labile iron pool, promote the accumulation of cellular ROS 通过调节 AMPK/mTOR/70 kDa 核糖体蛋白 S6 激酶（p70S6K）信号通路的活性诱导自噬，加速铁蛋白降解，增加易溶铁库，促进细胞 ROS 的积累 |
| ATPR | AML | ROS-autophagy-lysosomal pathway ROS- 自噬-溶酶体途径 |
| Aldh3a2 | AML | Aldh3a2 knockout changes the redox state of cells, affects lipid metabolism, and combines with GPX4 inhibition to activate ferroptosis Aldh3a2 基因敲除改变了细胞的氧化还原状态，影响了脂质代谢，并与 GPX4 抑制作用相结合，激活了铁变态反应 |
| Sulfasalazine | AML | Inhibit cystine importer SLC7A11/xCT and lead to depletion of GSH bank and oxidative stress-dependent cell death 抑制胱氨酸导入器 SLC7A11/xCT，导致 GSH 库耗竭和依赖氧化应激的细胞死亡 |
| Typhaneoside | AML | Induce autophagy by promoting the activation of the AMPK signal pathway and then increase the labile iron pool and promote the accumulation of cellular ROS 通过促进 AMPK 信号通路的激活来诱导自噬，进而增加易溶铁库并促进细胞 ROS 的积累 |
| Chlorido[N,N΄-disalicylidene-1,2-phenylenediamine] iron(III) complexes 氯[N,N΄-二水杨醛-1,2-苯二胺]铁(III)络合物 | AML | Increase the production of ROS 增加 ROS 的产生 |
| Ungeremine | AML | Activate caspase, change metalloproteinases, increase ROS production 激活 Caspase，改变金属蛋白酶，增加 ROS 的产生 |
| Epunctanone | AML | The addition of deferoxamine or ferrostatin-1 decreased its cytotoxicity 添加去铁胺或铁前列素-1 会降低其细胞毒性 |
| Natural triterpene saponin ardisiacrispin B 天然三萜皂苷 ardisiacrispin B | AML | The addition of deferoxamine or ferrostatin-1 decreased its cytotoxicity 添加去铁胺或铁前列素-1 会降低其细胞毒性 |
| HD | ALL | Increase the accumulation of ROS and decrease GSH and GPX4 增加 ROS 的积累，减少 GSH 和 GPX4 |
| SCHL | ALL | The addition of deferoxamine or ferrostatin-1 decreased its cytotoxicity 添加去铁胺或铁前列素-1 会降低其细胞毒性 |
| Aridanin | ALL | The addition of deferoxamine or ferrostatin-1 decreased its cytotoxicity 添加去铁胺或铁前列素-1 会降低其细胞毒性 |
| PAA | T-ALL | Increase ROS production, induce autophagy through AMPK/mTOR and LC3 signaling pathways, and cause GSH downregulation 增加 ROS 生成，通过 AMPK/mTOR 和 LC3 信号通路诱导自噬，并导致 GSH 下调 |
Aldh3a2: aldehyde dehydrogenase 3a2; ALL: Acute lymphocytic leukemia; AML: Acute myeloid leukemia; AMPK: Adenosine monophosphate-activated protein kinase; ATPR: 4-Amino-2-trifluoromethyl-phenyl retinate; DHA: Dihydroartemisinin; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HD: Hydnocarpin D; LC3: Microtubule-associated protein 1 light chain 3; mTOR: Mechanistic target of rapamycin; PAA: Poricoic acid A; ROS: Reactive oxygen species; SCHL: Soyauxinium chloride; SLC7A11: Solute carrier family 7 member 11; T-ALL: T cell ALL; xCT: System Xc- consists of light chain subunit SLC7A11.
Aldh3a2：醛脱氢酶 3a2；ALL：急性淋巴细胞白血病；AML：急性淋巴细胞白血病：急性淋巴细胞白血病; AML：AMPK：单磷酸腺苷激活的蛋白激酶；ATPR：4-氨基-2-三氟甲基苯基视黄酸；DHA：二氢青蒿素；GPX4：谷胱甘肽过氧化物酶 4；GSH：谷胱甘肽；HD：水黄素 D；LC3：微管相关蛋白 1 轻链 3；mTOR：雷帕霉素机制靶点；PAA：茯苓酸 A；ROS：氧化还原酶：ROS： 活性氧SLC7A11：溶质运载家族 7 成员 11；T-ALL：T 细胞 ALL；xCT：System Xc-由轻链亚基 SLC7A11 组成。
AML
Long non-coding ribonucleic acids (lncRNAs) are transcripts of >200 nucleotides and usually do not encode proteins. They play important physiological roles in the body and can regulate epigenetics, the cell cycle, and cell differentiation. Previous studies have shown that lncRNAs can participate in the process of iron-related death in tumors.[105–108] Zheng et al[109] identified seven lncRNAs (AP001266.2, AC133961.1, AF064858.3, AC007383.2, AC008906.1, AC026771.1, and KIF26B-AS1) associated with ferroptosis. Those lncRNAs are related to GSH metabolism and tumor immunity and have been proven to be able to predict the prognosis of AML, providing insights for the development of new AML treatment strategies. Wang et al[110] found a nuclear lncRNA (LINC00618) with low expression in leukemia but high expression after vincristine (VCR) treatment. LINC00618 can accelerate ferroptosis by increasing the levels of lipid ROS and iron, reducing the expression of solute carrier family 7 member 11 (SLC7A11) and inhibiting the expression of lymphoid-specific helicase (LSH) (LSH inhibits iron-related death by enhancing transcription after recruitment to the promoter region of SLC7A11). In addition, LINC00618 can promote ferroptosis and apoptosis induced by VCR, and LINC00618 can accelerate the occurrence of iron-related death through apoptosis.
长非编码核糖核酸（lncRNA）是大于 200 个核苷酸的转录本，通常不编码蛋白质。它们在体内发挥着重要的生理作用，可以调节表观遗传学、细胞周期和细胞分化。以往的研究表明，lncRNAs可参与肿瘤中与铁有关的死亡过程。 [105–108] Zheng 等人 [109] 发现了 7 个与铁凋亡相关的 lncRNA（AP001266.2、AC133961.1、AF064858.3、AC007383.2、AC008906.1、AC026771.1 和 KIF26B-AS1）。这些lncRNA与GSH代谢和肿瘤免疫有关，已被证实能预测AML的预后，为开发新的AML治疗策略提供启示。Wang 等人 [110] 发现了一种核 lncRNA（LINC00618），它在白血病中低表达，但在长春新碱（VCR）治疗后高表达。LINC00618 可通过增加脂质 ROS 和铁的水平、降低溶质运载家族 7 成员 11（SLC7A11）的表达和抑制淋巴细胞特异性螺旋酶（LSH）的表达（LSH 在招募到 SLC7A11 启动子区域后通过增强转录抑制铁相关死亡）来加速铁变态反应。此外，LINC00618 还能促进 VCR 诱导的铁凋亡和细胞凋亡，LINC00618 还能通过细胞凋亡加速铁相关死亡的发生。
Bioinformatics databases play an increasingly important role in cancer research. Chen et al[11] used ferroptosis-related genes to distinguish two subtypes in the the cancer genome atlas (TCGA) cohort. From the differentially expressed gene (DEG) analysis of these two subtypes, they established an AML prediction model containing 13 genes (ATG3, FAM106A, KLHL9, LCMT2, LRRC40, LZTR1, NCR2, PAFAH2, PCMTD2, PLA2G5, SCARB1, TK1, ZNF576), which was verified in an independent AML cohort. At the same time, the model can also provide a reference for identifying the sensitivity of chemotherapy drugs and ferroptosis inducers in high-risk groups and low-risk groups. It has the potential value for clinical transformation. In conclusion, these works have revealed the specific relationship between ferroptosis and AML, which may help clinical treatment in the future.
生物信息学数据库在癌症研究中发挥着越来越重要的作用。Chen等人 [11] ，利用铁突变相关基因区分了癌症基因组图谱（TCGA）队列中的两个亚型。通过对这两种亚型的差异表达基因（DEG）分析，他们建立了一个包含13个基因（ATG3、FAM106A、KLHL9、LCMT2、LRRC40、LZTR1、NCR2、PAFAH2、PCMTD2、PLA2G5、SCARB1、TK1、ZNF576）的AML预测模型，并在一个独立的AML队列中进行了验证。同时，该模型还能为确定化疗药物和铁蛋白诱导剂在高危人群和低危人群中的敏感性提供参考。它具有潜在的临床转化价值。总之，这些研究揭示了铁蛋白沉积与急性髓细胞白血病之间的特殊关系，可能有助于未来的临床治疗。
p53 is a well-known tumor suppressor and plays an important role in regulating ferroptosis.[1,112] Some studies have found that the circular RNAs of lysine-specific demethylase 4C (circKDM4C) is downregulated in AML and inhibits the proliferation, migration, and invasion of AML cells. In addition, the upregulation of p53 expression by circKDM4C via hsa-let-7b-5p can reduce ferroptosis.[113] As a promising drug, eprenetapopt (APR-246) can target the mutant protein p53 in AML and promote its binding to target DNA to restore p53 transcriptional activity.[114–118] Birsen et al[119] have shown that AML cell death induced by APR-246 can be inhibited by iron-chelating agents, lipophilic antioxidants, and lipid peroxidation inhibitors, indicating that APR-246 can induce ferroptosis of AML cells. The combination of APR-246 and ferroptosis inducers has synergistic anti-leukemic activity in vitro, and inactivation of the SLC7A11 gene and APR-246 treatment have synergistic anti-leukemic activity in vivo.[119]
p53 是一种众所周知的肿瘤抑制因子，在调节铁变态反应方面发挥着重要作用。 [1,112] 有研究发现，赖氨酸特异性去甲基化酶 4C 的环状 RNA（circKDM4C）在 AML 中下调，并抑制 AML 细胞的增殖、迁移和侵袭。此外，circKDM4C通过hsa-let-7b-5p上调p53的表达，可以减少铁变态反应。 [113] 作为一种很有前景的药物，eprenetapopt（APR-246）可以靶向 AML 中的突变蛋白 p53，促进其与靶 DNA 结合，从而恢复 p53 的转录活性。 [114–118] Birsen等人 [119] ，研究表明APR-246诱导的AML细胞死亡可以被铁螯合剂、亲脂抗氧化剂和脂质过氧化抑制剂所抑制，这表明APR-246可以诱导AML细胞的铁突变。APR-246与铁突变诱导剂联合使用在体外具有协同抗白血病活性，SLC7A11基因失活与APR-246治疗在体内具有协同抗白血病活性。 [119]
The GPX family of enzymes has peroxidase activity. The abnormal expression of GPXs is related to the occurrence and development of tumors.[120,121] Functional enrichment analysis showed that cells with differential expression of GPXs were mainly enriched in oxidative stress, immune regulation, and inflammation, in addition to GSH metabolism and ferroptosis.[122] GPX1 is an important member of the GPX family and is closely related to the occurrence and development of tumors.[123,124] Studies have shown that GPX1 is highly expressed in AML, and high GPX1 expression is associated with poor prognosis. In AML, GPX1 is involved in signal transduction processes such as GSH metabolism and ferroptosis.[125]
GPX 酶家族具有过氧化物酶活性。GPXs 的异常表达与肿瘤的发生和发展有关。 [120,121] 功能富集分析表明，GPXs差异表达的细胞主要富集于氧化应激、免疫调节和炎症，此外还富集于GSH代谢和铁变态反应。 [122] GPX1 是 GPX 家族的重要成员，与肿瘤的发生和发展密切相关。 [123,124] 研究表明，GPX1 在急性髓细胞性白血病中高表达，而 GPX1 的高表达与预后不良有关。在急性髓细胞性白血病中，GPX1参与了GSH代谢和铁变态反应等信号转导过程。 [125]
By querying the metabolic pathways related to leukemia stem cells and survival rate in multiple AML data sets, Itzykson et al[126] determined that SLC7A11 is related to the poor prognosis of AML, and SLC7A11 can promote the survival of AML cells by encoding xCT cystine importer. The drug sulfasalazine with xCT inhibitory activity has anti-leukemia activity, which can lead to depletion of the GSH bank and oxidative stress-dependent cell death (partially related to ferroptosis). More importantly, in vivo and in vitro experiments confirmed that the combination of anthracycline daunorubicin and sulfasalazine has the best anti-AML effect, indicating that targeting cystine import can be used for AML treatment, and sulfasalazine combined with chemotherapy is a promising treatment strategy for AML patients in the future.[126]
通过查询多个急性髓细胞白血病数据集中与白血病干细胞和存活率相关的代谢通路，Itzykson等人 [126] ，确定SLC7A11与急性髓细胞白血病的不良预后有关，SLC7A11可通过编码xCT胱氨酸导入器促进急性髓细胞白血病细胞的存活。具有 xCT 抑制活性的药物柳氮磺胺吡啶具有抗白血病活性，可导致 GSH 库耗竭和氧化应激依赖性细胞死亡（部分与铁变态反应有关）。更重要的是，体内和体外实验证实，蒽环类药物达乌鲁比星和柳氮磺胺吡啶联合使用具有最佳的抗AML效果，这表明靶向胱氨酸输入可用于AML治疗，柳氮磺胺吡啶联合化疗是未来AML患者的一种有希望的治疗策略。 [126]
The human immunodeficiency virus type I enhancer binding protein (HIVEP) family has been proven to be involved in many biological processes, such as cell survival, tumor necrosis factor (TNF) signal transduction, and tumor formation. However, its expression pattern, prognostic relevance, and functional significance in AML remain unclear. Ma's team found in the database that the increased transcription level of HIVEP3 in AML patients is an independent factor affecting the poor prognosis of AML patients, and is related to AML subtype, age, cytogenetic risk, and disease-related molecules.[127] The HIVEP3 co-expression gene cluster is rich in functional pathways related to AML leukemia. Further cell experiments showed that HIVEP3 messenger RNA (mRNA) and protein levels were abnormally expressed in leukemia cells and primitive cells in bone marrow tissue, and HIVEP3 participated in the iron cell apoptosis signal pathway. The research shows that HIVEP3 can be used as an independent prognostic indicator for AML patients. Targeting HIVEP3 to affect the iron death signal pathway of AML may provide a new scheme for AML treatment.[127]
人类免疫缺陷病毒 I 型增强子结合蛋白（HIVEP）家族已被证实参与了许多生物学过程，如细胞存活、肿瘤坏死因子（TNF）信号转导和肿瘤形成。然而，它在急性髓细胞性白血病中的表达模式、预后相关性和功能意义仍不清楚。Ma的团队在数据库中发现，HIVEP3在AML患者中的转录水平升高是影响AML患者不良预后的独立因素，并与AML亚型、年龄、细胞遗传学风险和疾病相关分子有关。 [127] HIVEP3共表达基因簇富含与AML白血病相关的功能通路。进一步的细胞实验表明，HIVEP3信使RNA（mRNA）和蛋白水平在骨髓组织中的白血病细胞和原始细胞中异常表达，HIVEP3参与了铁细胞凋亡信号通路。研究表明，HIVEP3可作为急性髓细胞白血病患者的独立预后指标。以HIVEP3为靶点影响急性髓细胞白血病的铁死亡信号通路，可能为急性髓细胞白血病的治疗提供一种新方案。 [127]
Erastin is a quinazolinone derivative that was found when attempting to identify small synthetic lethal molecules to be used for cells with RAS oncogene expression. In addition, erastin can induce ferroptosis in tumor cells.[1,30] Yu et al[128] found that erastin-induced ferroptosis in HL-60 cells in a dose-dependent manner and enhanced the sensitivity of AML cells to chemotherapeutic drugs such as cytarabine and doxorubicin in a RAS-independent manner, providing a possible solution for AML drug resistance. Previous reports have shown that the transcription factor high mobility group protein 1 (HMGB1) plays an important role in the pathogenesis and chemotherapy resistance of leukemia.[129–133] Ye et al[134] showed that HMGB1 can regulate erastin-induced ferroptosis in HL-60/NRASQ61L cells through the Ras- jun N-terminal kinase (JNK)/p38 signaling pathway, informing the mechanism by which HMGB1 modulates ferroptosis in leukemia.
厄拉斯汀是一种喹唑啉酮衍生物，是在试图确定用于表达 RAS 癌基因的细胞的小型合成致死分子时发现的。此外，厄拉斯汀还能诱导肿瘤细胞发生铁变态反应。 [1,30] Yu 等人 [128] 发现，依拉斯汀能以剂量依赖的方式诱导 HL-60 细胞的铁突变，并以 RAS 无关的方式增强 AML 细胞对胞磷胆碱和多柔比星等化疗药物的敏感性，为 AML 耐药性的解决提供了可能。以往的报道显示，转录因子高迁移率基团蛋白1（HMGB1）在白血病的发病机制和化疗耐药中起着重要作用。 [129–133] Ye 等人的研究 [134] 表明，HMGB1 可通过 Ras- jun N 端激酶（JNK）/p38 信号通路调控厄洛斯汀诱导的 HL-60/NRASQ61L 细胞的铁突变，从而揭示了 HMGB1 调节白血病铁突变的机制。
The resistance of tumor cells to existing anticancer drugs hinders the success of tumor chemotherapy. Many natural products show cytotoxicity against tumor cells. Ungeremine induces ferroptosis by activating caspases, changing the mitochondrial membrane potential (MMP), and increasing ROS production.[135] Typhanthin (typhneoside, TYP) is the main flavonoid in the extract of pollen typhae. In AML, TYP can activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, induce autophagy, accelerate the accumulation of ferritin, promote the accumulation of ROS, and eventually lead to ferroptosis.[136] Mbaveng et al[137] showed that epunctanone induces apoptosis and ferroptosis in CCRF-CEM cells by changing the MMP and increasing ROS production.
肿瘤细胞对现有抗癌药物的抗药性阻碍了肿瘤化疗的成功。许多天然产品对肿瘤细胞具有细胞毒性。钩藤碱通过激活 Caspases、改变线粒体膜电位（MMP）和增加 ROS 的产生来诱导铁变态反应。 [135] 酪黄素（酪烯苷，TYP）是酪梨花粉提取物中的主要黄酮类化合物。在 AML 中，TYP 可激活单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）信号通路，诱导自噬，加速铁蛋白的积累，促进 ROS 的积累，并最终导致铁变态反应。 [136] Mbaveng 等人的研究 [137] 表明，表巴酮通过改变 MMP 和增加 ROS 的产生，诱导 CCRF-CEM 细胞凋亡和铁凋亡。
The naturally occurring oleanane-type triterpene saponin ardisiacrispin B, isolated from the fruit of Ardisia kivuensis Taton (Myrsinaceae), induces apoptosis and ferroptosis of CCRF-CEM cells by activating promoter caspases 8 and 9 and effector caspases 3 and 7, modulating the MMP, and increasing the production of ROS.[138]
从 Ardisia kivuensis Taton（Myrsinaceae）果实中分离出的天然齐墩果烷型三萜皂苷 ardisiacrispin B 可通过激活启动子 caspases 8 和 9 以及效应子 caspases 3 和 7、调节 MMP 和增加 ROS 的产生，诱导 CCRF-CEM 细胞凋亡和铁凋亡。 [138]
In addition to some natural products that can induce ferroptosis in AML, some compounds, molecules, and artificially designed drugs can also be useful. One study has shown that the expression level of adrenomedullin (ADM) is related to the expression of genes involved in leukemogenesis, cell proliferation regulation, and ferroptosis, providing insights for further exploration of new therapeutic strategies for AML.[139] Dihydroartemisinin (DHA) has been reported to inhibit the growth of lymphocytic leukemia.[140] However, the mechanism of its action in AML is not clear. Du et al[141] found that DHA can activate autophagy, promote ferritin-related lysis, and increase intracellular ROS accumulation by affecting the activity of the AMPK/mTOR (mTOR: Mechanistic target of rapamycin)/70 kDa ribosomal protein S6 kinase (p70S6K) signaling pathway, ultimately leading to ferroptotic cell death. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR) is an all-trans retinoic acid (ATRA) derivative designed by Li et al[142] and has been shown to be more effective than ATRA in many tumors. ATPR has also been found to cause autophagy-induced ferroptosis in vivo and in vitro in studies targeting AL.[142–148] Leukemic cells prevent oxidative damage by oxidizing long-chain aliphatic aldehydes via aldehyde dehydrogenase 3a2 (Aldh3a2). The study of Yusuf et al[149] shows that knocking down Aldh3a2 can affect the lipid metabolism and redox state of AML cells and induce ferroptosis. Importantly, ferroptosis caused by Aldh3a2 depletion have a synergistic effect with the inhibition of GPX4, which may provide a theoretical basis for the combined application of Aldh3a2 inhibitors and cytotoxic therapy.[149] In recent years, iron-based nanodrugs have become a new type of ferroptosis inducer in leukemia.[150–152] Luo et al[153] studied the effects of two kinds of iron nanoparticles, 2,3-dimercaptosuccinic acid (DMSA)-coated Fe3O4 nanoparticles (FeNPs) as a ROS inducer and Prussian blue nanoparticles (PBNPs) as a ROS scavenger, on the transcripts of two kinds of leukemic cells (KG1a AML cells and HL60 acute promyelocytic leukemia cells). According to the results, there were 14 common upregulated genes and 4 common downregulated genes; of these genes, FTL, DNM1, and transferrin receptor (TRFC) play an important role in iron metabolism, indicating that the two drugs may cause cytotoxicity to leukemic cells through ferroptosis. It has been reported that the chloro [N-methylethyl] iron(III) complex produces lipid-based ROS and induces ferroptotic cell death in leukemic and neuroblastoma cell lines, suggesting that it can be used as a novel inducer of ferroptosis in leukemic and neuroblastoma cell lines.[154]
除了一些天然产物能诱导急性髓细胞性白血病的铁变态反应外，一些化合物、分子和人工设计的药物也能发挥作用。一项研究表明，肾上腺髓质素（ADM）的表达水平与参与白血病发生、细胞增殖调节和铁变态反应的基因表达有关，这为进一步探索治疗急性髓细胞性白血病的新策略提供了启示。 [139] 据报道，双氢青蒿素（DHA）可抑制淋巴细胞白血病的生长。 [140] 然而，其在急性髓细胞性白血病中的作用机制尚不清楚。Du 等人 [141] 发现，DHA 可通过影响 AMPK/mTOR（mTOR：雷帕霉素机制靶点）/70 kDa 核糖体蛋白 S6 激酶（p70S6K）信号通路的活性，激活自噬，促进铁蛋白相关溶解，并增加细胞内 ROS 的积累，最终导致铁蛋白细胞死亡。4-氨基-2-三氟甲基苯基视黄酸（ATPR）是Li等人设计的一种全反式视黄酸（ATRA）衍生物 [142] ，已被证明对许多肿瘤比ATRA更有效。在针对 AL 的研究中，还发现 ATPR 在体内和体外都能引起自噬诱导的铁变态反应。 [142–148] 白血病细胞通过醛脱氢酶 3a2（Aldh3a2）氧化长链脂肪醛，从而防止氧化损伤。Yusuf 等人的研究 [149] 表明，敲除 Aldh3a2 可影响 AML 细胞的脂质代谢和氧化还原状态，并诱导铁变态反应。重要的是，Aldh3a2耗竭引起的铁突变与GPX4的抑制具有协同作用，这可能为Aldh3a2抑制剂与细胞毒疗法的联合应用提供理论依据。 [149] 近年来，铁基纳米药物已成为一种新型的白血病铁突变诱导剂。 [150–152] Luo等人 [153] 研究了2,3-二巯基丁二酸（DMSA）包裹的Fe 3 O 4 纳米颗粒（FeNPs）作为ROS诱导剂和普鲁士蓝纳米颗粒（PBNPs）作为ROS清除剂这两种铁纳米颗粒对两种白血病细胞（KG1a AML细胞和HL60急性早幼粒细胞白血病细胞）转录本的影响。结果显示，有14个常见基因上调，4个常见基因下调，其中FTL、DNM1和转铁蛋白受体（TRFC）在铁代谢中起重要作用，表明这两种药物可能通过铁跃迁作用对白血病细胞产生细胞毒性。据报道，氯[N-甲基乙基]铁(III)复合物可产生脂基 ROS 并诱导白血病细胞系和神经母细胞瘤细胞系发生铁突变细胞死亡，这表明它可用作白血病细胞系和神经母细胞瘤细胞系铁突变的新型诱导剂。 [154]
ALL
ALL is a common hematological tumor characterized by the malignant proliferation of lymphoid progenitor cells. Many important factors are involved in the regulation of ALL.[155,156] It has been reported that the progestin and adipoq receptor family member 3 (PAQR3), a tumor suppressor, inhibits the proliferation and induces apoptosis of human leukemia cells, but its effect on cell proliferation and iron-related death and related regulatory mechanisms needs to be further studied.[157] Jin et al[158] showed that low expression of PAQR3 in ALL inhibits the proliferation of ALL cells and aggravates ferroptosis. Further experiments showed that PAQR3 binds to NRF2 and regulates its expression in ALL through ubiquitination, thus affecting cell proliferation and ferroptosis. ALL is closely related to ferroptosis. Marcotte's team performed whole-genome CRISPR/Cas deletion screening on a panel of seven B-ALL cell lines.[159] The results showed that compared with other cancers, the survival of ALL cell lines depended on several unique metabolic pathways, including sensitivity to GPX4 depletion and induction of iron cell apoptosis. Detailed molecular analysis showed that B-ALL cells showed high steady-state oxidative stress potential, low buffer capacity, and GPX4-independent secondary lipid peroxidation detoxification pathway, suggesting that they were sensitive to ferroptosis. Finally, Marcotte used samples from B-ALL patients to verify that B-ALL is indeed sensitive to iron-related apoptosis.[159]
ALL 是一种常见的血液肿瘤，其特征是淋巴祖细胞的恶性增殖。许多重要因素参与了 ALL 的调控。 [155,156] 有报道称，孕激素和脂肪q受体家族成员3（PAQR3）是一种肿瘤抑制因子，可抑制人类白血病细胞的增殖并诱导其凋亡，但其对细胞增殖和铁相关死亡的影响及相关调控机制有待进一步研究。 [157] Jin 等人的研究 [158] 表明，PAQR3 在 ALL 中的低表达会抑制 ALL 细胞的增殖并加重铁变态反应。进一步的实验表明，PAQR3与NRF2结合，通过泛素化调控NRF2在ALL中的表达，从而影响细胞增殖和铁变态反应。ALL 与铁突变密切相关。Marcotte的团队对七种B-ALL细胞系进行了全基因组CRISPR/Cas缺失筛选。 [159] 结果显示，与其他癌症相比，ALL细胞系的存活取决于几种独特的代谢途径，包括对GPX4消耗的敏感性和诱导铁细胞凋亡。详细的分子分析表明，B-ALL细胞表现出高稳态氧化应激电位、低缓冲能力和不依赖GPX4的次级脂质过氧化解毒途径，这表明它们对铁凋亡很敏感。最后，Marcotte利用B-ALL患者的样本验证了B-ALL确实对与铁有关的细胞凋亡敏感。 [159]
Ferroptosis is characterized by the generation of lipid-based ROS and lipid peroxidation.[160] Several ROS-generating enzymes contain iron or iron derivatives as essential cofactors for their proper function, such as LOX, nicotinamide adenine dinucleotide phosphate hydride (NADPH) oxidase (NOX), xanthine oxidase, and cytochrome P450 enzymes.[6] LOXs are key enzymes that catalyze the oxygenation of polyunsaturated fatty acyl groups to lipid hydroperoxides,[161] while GPX family members are responsible for the reduction of hydrogen and lipid peroxides.[162] It is also reported that the regulatory effect of LOXs on RSL3-induced ferroptosis in ALL cells. Their research indicates that RSL3, an inhibitor of GPX4, triggers lipid peroxidation, ROS generation, and cell death in ALL cells. All of these events were prevented by the presence of iron statin-1 (Fer-1), a small molecular inhibitor of lipid peroxidation. Importantly, LOX inhibitors, including the selective LOX12/15 inhibitor baicalein and the pan-LOX inhibitor nordihydroguaiaretic acid (NDGA), protect cells from RSL3-stimulated lipid peroxidation, ROS production, and cell death, suggesting that LOXs contribute to ferroptosis.[163]
铁变态反应的特点是产生基于脂质的 ROS 和脂质过氧化。 [160] 一些产生 ROS 的酶含有铁或铁衍生物作为其正常功能所必需的辅助因子，如 LOX、烟酰胺腺嘌呤二核苷酸磷酸氢化物（NADPH）氧化酶（NOX）、黄嘌呤氧化酶和细胞色素 P450 酶。 [6] LOXs 是催化多不饱和脂肪酰基氧化为脂质氢过氧化物的关键酶， [161] ，而 GPX 家族成员则负责还原氢和脂质过氧化物。 [162] 另据报道，LOXs 对 RSL3 诱导的 ALL 细胞铁变态反应有调节作用。他们的研究表明，GPX4 的抑制剂 RSL3 会引发 ALL 细胞的脂质过氧化、ROS 生成和细胞死亡。铁他汀-1（Fer-1）是一种小分子脂质过氧化抑制剂，它的存在可阻止所有这些事件的发生。重要的是，LOX抑制剂（包括选择性LOX12/15抑制剂黄芩苷和泛LOX抑制剂去氢瓜氨酸（NDGA））能保护细胞免受RSL3刺激的脂质过氧化、ROS生成和细胞死亡的影响，这表明LOXs有助于铁变态反应。 [163]
Previously, many natural extracts were shown to be involved in the induction of ferroptosis in AML. In ALL, some compounds and drug components are also associated with ferroptosis. Hydnocarpin D (HD) is a bioactive flavonoid lignin with good antitumor activity.[164,165] HD inhibits the proliferation of the T cell ALL (T-ALL) cell lines Jurkat and Molt-4 in vitro by inducing cell cycle arrest, which results in apoptosis. In addition, HD increases the level of microtubule-associated protein light chain 3 (LC3)-II, a marker of autophagy, and the formation of autophagic lysosomal vacuoles. The inhibitory effect of ATG5/7 gene knockout or 3-MA pretreatment on autophagy partially enhanced the apoptosis induced by HD, suggesting that autophagy enhances the influence of HD. Moreover, this cytotoxic autophagy caused ferroptosis, which was characterized by the accumulation of lipid ROS and a decrease in GSH and GPX4, and conversely, inhibition of autophagy hindered cell ferroptosis.[166] Soyauxinium chloride (SCHL) is a naturally occurring indole-quinazoline-type alkaloid. Some studies found that SCHL induced cytotoxicity of CCRF-CEM leukemia cells through caspase 3, 7, 8, and 9 activation, MMP alteration, and increased ROS generation, while the presence of Fer-1 (ferrostain-1) or DFA (deferoxamine; an iron-related death inhibitor) decreased SCHL cytotoxicity by 7.11- and 4.64-fold, respectively, indicating that SCHL is involved in ferroptosis.[167] Similarly, a naturally occurring N-acetylated oleanolic acid glycoside (aridanin) was cytotoxic to CCRF-CEM leukemia cells, and when nec-1 (necrosis inhibitor), Fer-1 (iron-related death inhibitor), and DFA (iron-related death inhibitor) were added, allicin was 2.74-, 1.61-, and 2.70-fold less cytotoxic, respectively, indicating its ability to induce necrosis and ferroptosis in CCRF-CEM cells.[168] Poricoic acid A (PAA) is the main chemical component of the surface layer of mushroom Poria cocos, which has a protective effect on various diseases. Sun et al[169] found that PAA can trigger apoptosis of T-ALL cells by increasing ROS production, induce autophagy through AMPK/mTOR and LC3 signaling pathways, and cause GSH downregulation and malonaldehyde (MDA) upregulation, leading to ferroptosis. The in vitro experiments also confirmed the inhibitory effect of PAA on T-ALL, indicating that PAA may be a new therapeutic strategy for patients with T-ALL.
以前，许多天然提取物被证明参与了急性髓细胞性白血病的铁变态反应诱导。在 ALL 中，一些化合物和药物成分也与铁变态反应有关。Hydnocarpin D（HD）是一种生物活性黄酮类木质素，具有良好的抗肿瘤活性。 [164,165] HD 通过诱导细胞周期停滞，导致细胞凋亡，从而抑制体外 T 细胞 ALL（T-ALL）细胞系 Jurkat 和 Molt-4 的增殖。此外，HD还能提高自噬标记物微管相关蛋白轻链3（LC3）-II的水平，并促进自噬溶酶体空泡的形成。ATG5/7 基因敲除或 3-MA 预处理对自噬的抑制作用部分增强了 HD 诱导的细胞凋亡，表明自噬增强了 HD 的影响。此外，这种细胞毒性自噬还会引起铁变态反应，其特征是脂质 ROS 的积累以及 GSH 和 GPX4 的减少；反之，抑制自噬则会阻碍细胞的铁变态反应。 [166] 氯化大豆异黄酮（SCHL）是一种天然的吲哚喹唑啉类生物碱。一些研究发现，SCHL 通过 caspase 3、7、8 和 9 激活、MMP 改变和 ROS 生成增加诱导 CCRF-CEM 白血病细胞的细胞毒性，而 Fer-1（铁锈色素-1）或 DFA（去铁胺，一种铁相关死亡抑制剂）的存在分别使 SCHL 的细胞毒性降低了 7.11 倍和 4.64 倍，这表明 SCHL 参与了铁凋亡。 [167] 同样，一种天然存在的 N-乙酰化齐墩果酸苷（大蒜素）对 CCRF-CEM 白血病细胞具有细胞毒性，当加入 nec-1（坏死抑制剂）、Fer-1（铁相关死亡抑制剂）和 DFA（铁相关死亡抑制剂）时，大蒜素的细胞毒性分别降低了 2.74倍、1.61倍和2.70倍，这表明大蒜素具有诱导CCRF-CEM细胞坏死和铁突变的能力。 [168] 茯苓酸 A（PAA）是茯苓表层的主要化学成分，对多种疾病有保护作用。Sun 等人 [169] 发现，PAA 可通过增加 ROS 生成引发 T-ALL 细胞凋亡，通过 AMPK/mTOR 和 LC3 信号通路诱导自噬，并引起 GSH 下调和丙二醛（MDA）上调，导致铁变态反应。体外实验也证实了 PAA 对 T-ALL 的抑制作用，表明 PAA 可能是治疗 T-ALL 患者的一种新策略。
Adult T cell leukemia/lymphoma (ATLL)
成人 T 细胞白血病/淋巴瘤 (ATLL)
ATLL is an invasive disease caused by human T cell leukemia virus type 1 (HTLV-1) infection. The therapeutic effect in patients is limited by chemotherapy resistance. Therefore, there is an urgent need to develop new and effective strategies.[170,171] Artesunate (ART) is a widely used antimalarial compound that has been proven to have cytotoxicity.[172] However, the mechanism of its action in ATLL is not clear. Ishikawa et al[173] showed that ART has a cytotoxic effect on ATLL cells, which can be partially reversed by treatment with ROS scavengers, iron-chelating agents, and inhibitors of necrosis or ferroptosis, indicating that ART can induce ferroptosis in ATLL cells and kill tumor cells.
ATLL 是一种由人类 T 细胞白血病病毒 1 型（HTLV-1）感染引起的侵袭性疾病。患者的治疗效果受到化疗耐药性的限制。因此，迫切需要开发新的有效策略。 [170,171] 青蒿琥酯（ART）是一种广泛使用的抗疟化合物，已被证实具有细胞毒性。 [172] 然而，它对 ATLL 的作用机制尚不清楚。Ishikawa等人的研究 [173] 表明，ART对ATLL细胞具有细胞毒性作用，用ROS清除剂、铁螯合剂和坏死或铁凋亡抑制剂处理后可部分逆转这种作用，这表明ART可诱导ATLL细胞铁凋亡，杀死肿瘤细胞。
Others 其他
There are currently fewer studies on ferroptosis in chronic leukemia than in AL. Although it has been proven that typhanthin and Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) complexes can induce ferroptotic cell death in the K562 cell line (CML cells), sufficient experimental evidence is lacking. In the future, a large number of studies are needed to explain the role of ferroptosis in chronic lymphocytic leukemia (CLL) and chronic myelocytic leukemia (CML).[136,154]
与 AL 相比，目前有关慢性白血病铁变态反应的研究较少。虽然已证实斑蝥素和氯[N,N'-二水杨醛-1,2-苯二胺]铁（III）复合物能诱导 K562 细胞系（CML 细胞）中的铁突变细胞死亡，但还缺乏足够的实验证据。今后，还需要进行大量研究来解释铁变态反应在慢性淋巴细胞白血病（CLL）和慢性粒细胞白血病（CML）中的作用。 [136,154]
Conclusions and Perspectives
结论与展望
In this review, we provided the definition, basic characteristics, and history of ferroptosis, briefly described the mechanism of ferroptosis, illustrated the relationship between abnormal iron metabolism and leukemia illustrated the relationship between abnormal iron metabolism and leukemia, and focused on recent progress in the understanding of the role of ferroptosis in leukemia. At present, leukemia is one of the most common malignant tumors and major disorders affecting human health. In recent years, with advances in radiotherapy, chemotherapy, HSC transplantation, and the emergence of new treatments such as targeted therapy, biotherapy, and cell therapy, the prognosis of patients with leukemia has been greatly improved. However, due to various factors, the overall survival time of patients with leukemia is still very short, and new treatment strategies to improve the survival time of patients still need to be developed. Ferroptosis is a form of oxidative cell death characterized by accumulated iron and excessive lipid peroxidation. Previous studies of ferroptosis have shown outstanding antitumor effects. The tumor-inhibitory effect of ferroptosis in fibrosarcoma, prostate cancer, and osteosarcoma has been confirmed. Targeting ferroptosis may become another innovative therapeutic strategy for the treatment of tumors. There has been much research to reveal the mechanism and utility of ferroptosis in hematological malignant tumors. Many natural drug extracts show great cytotoxicity against leukemic cells by inducing ferroptosis. Some lncRNAs and circular RNAs (circRNAs) also show the ability to induce ferroptosis in hematological malignant tumors, and some molecules participate in ferroptosis by regulating key molecules such as TP53, NRF2, GPX4, and GSH, which regulate ferroptotic cell death. Moreover, in addition inducing leukemic cell death, inducing ferroptosis can also assist in treatment by increasing sensitivity to drugs and chemotherapy. However, we have only just begun to understand the role of ferroptosis in leukemia. The results of studies on the role of ferroptosis in leukemia are still deficient. In the future, more in-depth research on the mechanism of ferroptosis in leukemia will contribute to the development of effective anticancer drugs. There is still great potential for the study of ferroptosis in leukemia.
在这篇综述中，我们介绍了铁代谢异常的定义、基本特征和历史，简述了铁代谢异常的机制，阐述了铁代谢异常与白血病的关系，并重点介绍了近年来在认识铁代谢异常在白血病中的作用方面取得的进展。目前，白血病是最常见的恶性肿瘤之一，也是影响人类健康的主要疾病之一。近年来，随着放疗、化疗、造血干细胞移植以及靶向治疗、生物治疗、细胞治疗等新疗法的出现，白血病患者的预后得到了极大改善。然而，由于各种因素的影响，白血病患者的总体生存时间仍然很短，改善患者生存时间的新治疗策略仍有待开发。铁中毒是一种氧化性细胞死亡，其特点是铁积累和脂质过氧化反应过度。以往对铁变态反应的研究显示了突出的抗肿瘤效果。铁氧化对纤维肉瘤、前列腺癌和骨肉瘤的抑制作用已得到证实。以铁蛋白变性为靶点可能成为治疗肿瘤的另一种创新性治疗策略。为揭示血液系统恶性肿瘤中铁蛋白沉积的机制和作用，人们进行了大量研究。许多天然药物提取物通过诱导铁变态反应对白血病细胞显示出巨大的细胞毒性。一些lncRNAs和环状RNAs（circRNAs）也显示出诱导血液恶性肿瘤中铁细胞凋亡的能力，一些分子通过调节TP53、NRF2、GPX4和GSH等关键分子参与铁细胞凋亡，从而调控铁细胞凋亡。此外，除了诱导白血病细胞死亡外，诱导铁变态反应还能提高对药物和化疗的敏感性，从而有助于治疗。然而，我们才刚刚开始了解铁氧化在白血病中的作用。有关铁氧化在白血病中的作用的研究成果仍然不足。未来，对白血病中铁细胞凋亡机制的更深入研究将有助于开发有效的抗癌药物。白血病中的高铁血症研究仍大有可为。
Footnotes 脚注
Tianxin Lyu and Xudong Li contributed equally to this work.
柳天新和李旭东对本研究做出了同等贡献。
How to cite this article: Lyu TX, Li XD, Song YP. Ferroptosis in acute leukemia. Chin Med J 2023;136:886–898. doi: 10.1097/CM9.0000000000002642
本文引用方式Lyu TX, Li XD, Song YP.急性白血病中的铁变态反应。Doi: 10.1097/CM9.0000000000002642.
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