Abstract
研究表明，铁代谢和铁死亡影响了髓系肿瘤的发生发展，可以作为其治疗靶点。铁代谢失调存在于多种髓系肿瘤中：急性髓系白血病的预后与铁代谢分子的差异表达相关；伴随铁过载的骨髓增生异常综合征患者预后不良；骨髓增殖性肿瘤常表现为缺铁和红细胞增多共存，可通过靶向铁调素进行治疗。髓系肿瘤细胞容易受到活性氧积累的影响而发生氧化损伤，具有铁死亡敏感性。在急性髓系白血病和骨髓增生异常综合征中，铁死亡均具有抗肿瘤作用；在慢性髓系白血病中，靶向铁死亡可以逆转伊马替尼耐药。本文综述了髓系肿瘤发生发展中铁代谢水平的特征，以及铁死亡在其中的作用机制，以期为开发治疗新策略提供依据。
Keywords: 髓系肿瘤, 铁代谢, 铁死亡, 机制, 综述
Abstract
It is reported that iron metabolism and ferroptosis can influence the occurrence and development of myeloid tumors, which can serve as therapeutic targets. Dysregulation of iron metabolism is present in a variety of myeloid neoplasms. The prognosis of acute myeloid leukemia is related to differential expression of molecules related to iron metabolism. The prognosis of myelodysplastic syndrome patients with iron overload is poor. Myeloproliferative neoplasms are often characterized by the coexistence of iron deficiency and erythrocytosis, which can be treated by targeting hepcidin. Myeloid tumor cells are susceptible to oxidative damage caused by the accumulation of reactive oxygen species and are sensitive to ferroptosis. Ferroptosis has anti-tumor effect in acute myeloid leukemia and myelodysplastic syndrome. Targeting ferroptosis can reverse imatinib resistance in chronic myeloid leukemia. This article reviews the characteristics of iron metabolism in the development and progression of myeloid neoplasms, as well as the mechanism of ferroptosis, to provide a basis for the development of new therapeutic strategies.
Keywords: Myeloid neoplasms, Iron metabolism, Ferroptosis, Mechanism, Review
髓系肿瘤是造血干细胞/祖细胞的一组异质性恶性肿瘤，主要包括AML、MPN、CML、PV、ET、PMF等以及MDS［1］。髓系肿瘤的预后情况不一。其中，AML患者疾病进展快，易出现化疗药物耐药和肿瘤复发等；部分MDS和MPN患者因具有向AML转化的高风险而预后不佳；部分CML患者出现酪氨酸激酶抑制剂耐药而加速了疾病进度，导致预后不良。因此，髓系肿瘤的治疗仍面临许多挑战。
铁是所有生物体及细胞基本代谢过程中的必需微量营养素。人体通过铁的吸收、回收和丢失的平衡来维持全身铁稳态［2］。通过巨噬细胞的吞噬作用而回收的铁是人体所需铁的主要来源，膳食中吸收的铁只占人体总铁需要量的4%~10%［3］。铁离子通过二价金属离子转运体-1和锌铁调节蛋白家族8/14转运进入肠上皮细胞，被还原为亚铁离子后通过铁转运蛋白输出到体循环［4-5］。循环中的铁与转铁蛋白结合后可被TFR识别，转运进入细胞后释放至不稳定铁池，细胞内过量铁被储存到FTH中［6］。铁调素由肝脏产生，通过尿液排泄，是全身铁稳态的主要调节因子。铁调素的合成受铁负荷、氧气水平和炎症信号的调节［7］，并通过诱导铁转运蛋白降解调控循环中的可用铁含量［8-9］。铁死亡是一种铁依赖的非凋亡性细胞死亡方式，其主要特征是由脂质过氧化物和活性氧的致命积累引起的细胞膜损伤，是与多种代谢途径相关的复杂生物过程［10］。
近年来，越来越多的研究发现髓系肿瘤中出现铁代谢紊乱，并提出铁死亡具有抗髓系肿瘤的作用。本文综述了铁代谢及铁死亡在主要髓系肿瘤中的最新研究进展，以期为髓系肿瘤的治疗提供新的思路及策略。
1. 铁代谢与髓系肿瘤
1.1. 铁代谢相关分子的差异表达与AML的预后有关
铁代谢失调与白血病的发生发展密切相关。白血病细胞通常表现出铁吸收增加和铁流出减少，导致细胞内铁水平较高［11］。同时，白血病患者常常因化疗引起红细胞生成障碍和贫血，需要输注大量红细胞，进一步升高不稳定铁池中铁离子水平，加剧铁超负荷［12］。细胞内铁含量过高会导致细胞内活性氧积累，导致氧化应激损伤，从而破坏DNA［11］。另外，白血病细胞需要大量铁来维持快速生长和增殖［11］。研究发现，铁稳态是治疗AML的有效靶点，铁螯合疗法可诱导白血病细胞分化和凋亡，而不损害正常细胞［13］。
AML患者的铁蛋白水平升高，尤其是急性粒单核细胞白血病患者和急性单核细胞白血病亚型患者。Yang等［14］发现，铁过载通过上调原癌基因FOS促进白血病细胞增殖，从而增加骨髓和髓外组织的肿瘤负荷，与AML患者的预后恶化和AML小鼠的生存时间缩短相关。过量铁和活性氧催化产物通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶和随后的GSH耗竭可促进造血干细胞恶性转化［15］。Lopes等［16］研究发现，AML不同于其他肿瘤类型和炎症性贫血，其主要表现为高铁蛋白、低转铁蛋白、高TSAT和高铁调素；AML诱导的成红细胞丢失是铁再分布和TSAT增加的原因。与Yang等［14］研究结果不同的是，Lopes等［16］研究发现全身性铁超负荷小鼠模型中AML进展延迟。TSAT或可作为AML的预后标志物，TSAT升高可能与AML机体总生存期延长独立相关。
AML患者中FTH1和铁蛋白轻链过表达，且FTH1可能通过NF-κB途径和促氧化途径导致耐药现象［17］。Yi等［18］研究发现，造血系统中FTH1的条件性缺失会导致铁水平降低、线粒体功能受损和细胞凋亡激活，最终减少造血干细胞数及降低其再生能力。补铁、抗氧化剂和细胞凋亡抑制剂可逆转FTH1缺失导致的造血干细胞活性降低。TFR1抑制引起的铁耗竭会阻断造血祖细胞增殖和分化，减弱造血干细胞的再生潜力［19］。而TFR1在白血病细胞中的表达普遍高于正常对照，且低分化AML倾向于表达更高水平TFR1［20］。TFR2在AML部分亚型（AML1、AML2和AML6）及CML中也上调。研究表明，TFR2表达水平升高可能与良好的预后呈正相关［21-22］。此外，Gasparetto等［23］发现，AML中铁转运蛋白低表达可能与较好的预后和较高的化疗敏感性相关。
白血病干细胞的静止细胞群能导致AML患者对细胞周期依赖性化疗药物的耐药。Larrue等［24］研究结果提示NCOA4介导的铁蛋白自噬在维持白血病干细胞静止和功能方面具有重要作用，提示靶向该途径可能成为AML的有效治疗策略。
1.2. MDS伴随铁过载提示预后不良
MDS是一种克隆性造血干细胞疾病，影响造血干细胞和早期多能祖细胞，导致造血分化失调。MDS的特点是外周血细胞减少，尤其是贫血和血小板减少［25］。MDS患者常伴随高铁负荷，所有MDS亚型的铁超负荷标志物（包括血清铁蛋白、TSAT、可溶性TFR等）均升高，且与不良预后相关［26-27］。多项研究结果表明，铁螯合疗法可以提高输血依赖性MDS患者的存活率，尤其是国际预后评分系统评价为低中危的患者［28］。Cremers等［29］指出，造血干细胞移植后早期减铁（6个月前开始）显著改善了MDS患者移植后的无复发生存期。研究发现MDS患者在输血依赖前就已经存在铁超负荷，提示铁代谢失调是疾病的内在因素［30］。这种原发性铁超负荷是由细胞凋亡率较高导致，多次红细胞输注会加剧铁超负荷，引发继发性铁超负荷［31］。继发性铁过载的形成往往需要一定时间，因此对于中位生存时间较长的低风险MDS患者发生铁相关并发症的风险较高［32］。铁过载还与白血病转化风险较高相关：铁过载诱导的氧化应激和遗传不稳定性可能在其中发挥关键作用，活性氧也可能促进MDS向AML转化［33-34］，但这仍需要更多研究进一步验证。
铁调素水平在不同MDS亚型间存在差异，其中环状铁粒幼细胞难治性贫血患者的铁调素水平最低，难治性贫血伴原始细胞过多和慢性粒单核细胞白血病患者的铁调素水平最高［35］。此外，输血会影响MDS患者血清铁调素水平，输血依赖的MDS患者的血调素水平随时间推移而升高，而非输血依赖的MDS患者的血调素水平随时间推移而降低［36］。Gu等［37］研究发现，地西他滨（一种去甲基化药物）可以改善MDS患者的原发性铁超负荷，对去甲基化治疗有反应的患者出现铁调素水平升高。研究表明，高血清铁调素水平与MDS患者病情严重以及低存活率相关［36］。但相关研究少，仍需要进一步证实。
鲜有研究报道铁过载与基因改变之间的关系。约50%的MDS患者中存在剪接体基因体细胞突变［38］。SF3B1突变是MDS中最常见的剪接因子突变，与MDS伴环形铁粒幼细胞亚型显著相关［38］。SF3B1突变与MDS的多种病理生理过程（如铁代谢）相关。分子研究表明，在SF3B1突变型MDS骨髓细胞中，铁稳态调节因子ABCB7、TMEM14C和ERFE通常被错接［38］。SF3B1突变可引起异常剪切，ABCB7和TMEM14C的表达下调，导致SF3B1突变型MDS的线粒体中铁积累增加、环形铁粒幼细胞增多［39］。Bondu等［40］研究发现，SF3B1突变型MDS患者存在SF3B1突变依赖的变异型ERFE+12转录本（该异常转录本在开放阅读框中包含12个额外的核苷酸），其产生的变异蛋白能抑制铁调素，这也会导致患者铁负荷增加。此外，一项针对中危和高危MDS患者的研究发现，铁过载的MDS患者中TET2和ASXL1基因突变的发生率较高［41］。这两种突变在MDS患者中很常见，与白血病的进展相关，且ASXL1是不良预后的独立预测因子［42］。然而，铁和/或活性氧是否与这些基因突变的产生有直接作用尚未明确，仍须进一步研究。
1.3. 铁调素可以作为MPN治疗靶点
费城染色体阴性MPN包括PV、ET和PMF。MPN患者频繁发生JAK-STAT信号通路相关突变，其中90%的PV患者以及50%~60%的ET和PMF患者存在JAK2
V617F突变［43］。Albayrak等［44］发现，与健康人群比较，MPN患者的生长分化因子15水平较高，线粒体铁蛋白1水平较低，但铁调素水平无差异。
PV是一种克隆性造血干细胞疾病，由JAK2-STAT5信号通路的促红细胞生成素超敏信号传导驱动，进而导致红细胞前体细胞过度增殖［43］。几乎所有PV患者在就诊时或病程中都存在缺铁，表现为缺铁和红细胞增多同时存在。尽管PV患者的铁调素受到相对抑制，但仍表现为铁缺乏，这可能是由于并发炎症、ERFE升高不足、铁调素抑制不足和/或肠道内异常缺氧信号阻止铁缺乏症恢复的综合影响所致［45］。PV患者需要反复进行静脉放血治疗，从而将血细胞比容控制在45%以下以降低血栓形成等并发症，而这会进一步加剧机体缺铁［46］。尽管缺铁，PV中的红细胞仍持续增多，这表明铁代谢紊乱是该疾病生物学的核心，为铁调素模拟物在PV中的应用提供了理论依据［47］。Bennett等［47］研究发现，PV患者中铁调素的上游调节因子HFE突变频繁存在，导致铁调素表达下调，铁过度吸收。铁调素上调可缓解PV的红系表型，而铁调素缺失可使其恶化。近年临床前及临床研究发现，使用铁调素模拟物（如rusfertide）或铁转运蛋白抑制剂治疗可以显著降低PV患者的放血治疗需求，控制红细胞增多和红细胞压积水平，增加全身铁储备［45， 48］。SLN124是一种N-乙酰半乳糖胺偶联的19-mer短干扰RNA，目前正在开发用于治疗铁负荷性贫血（包括β-地中海贫血、MDS）和MPN（如PV）。SLN124通过靶向肝脏和沉默TMPRSS6基因增加内源性铁调素合成。临床试验结果显示，健康人群对SLN124具有良好的耐受性和安全性［49］。
骨髓纤维化的特征主要是多能干细胞和祖细胞病理性增殖，生理性髓质红细胞生成环境被破坏，导致红细胞生成减少、进行性骨髓衰竭。Momelotinib是一种JAK1/JAK2激酶的小分子口服抑制剂。Chifotides等［50］研究发现，Momelotinib通过抑制ACVR1（一种与铁稳态密切相关的丝氨酸/苏氨酸激酶）来抑制铁调素表达，动员细胞储存铁并增强红细胞生成，可以降低PMF患者的输血依赖，改善贫血及脾肿大等全身症状。
2. 铁死亡与髓系肿瘤
2.1. 铁死亡具有抗AML作用
AML是一种复杂的疾病，涉及多种信号通路的激活。以往采用细胞毒药物的多药联合化疗，但易造成骨髓抑制、免疫破坏等严重不良后果。尽管FMS样酪氨酸激酶3抑制剂、维奈克拉和异柠檬酸脱氢酶抑制剂等靶向疗法在AML的治疗上显示出良好前景，但患者预后仍然较差。与其他肿瘤细胞比较，白血病细胞表现出较高的转铁蛋白表达，从而导致铁吸收增加和铁流出减少。这种现象使白血病细胞更易受活性氧积累的影响，从而导致不可挽回的过氧化损伤和铁死亡［51-52］。
研究发现越来越多的药物可以通过靶向铁死亡来诱导AML细胞死亡，可见铁死亡具有抗白血病活性。Yu等［53］发现，铁死亡激活剂Erastin可增强AML细胞对化疗药物（如阿糖胞苷和多柔比星）的敏感性，从而克服化疗耐药；其机制与Erastin通过激活丝裂原活化蛋白激酶信号通路诱导细胞铁死亡和坏死性凋亡相关。也有研究指出，在AML细胞和MDS细胞中，Erastin通过经典的氨基酸代谢途径诱导铁死亡，即抑制Xc－系统，降低GSH水平，导致活性氧水平升高［54］。SLC7A11是Xc－抗转运蛋白系统的重要组成部分，在细胞转运输出谷氨酸和转运输入胱氨酸的过程中发挥重要作用。抑制SLC7A11会引发铁死亡，其成为AML的潜在治疗策略。柳氮磺吡啶是一种常用药物，通过抑制SLC7A11、Xc－系统破坏氨基酸代谢平衡并耗尽抗氧化系统，最终导致活性氧依赖性细胞死亡，从而产生抗白血病作用［55］。研究发现，临床批准使用的酪氨酸激酶抑制剂索拉非尼也可以通过抑制Xc－系统而触发铁死亡［56］。化疗药物与SLC7A11靶向药物联合治疗为无法耐受AML强化疗的患者提供一种治疗选择。
5%~10%的AML存在P53突变。在具有复杂核型的患者中，P53异常的频率增加至70%~80%［57］。而抑癌基因P53在调节铁死亡中发挥重要作用。APR-246是一种靶向P53突变的新的治疗剂，可以靶向AML中的突变蛋白P53，并重新激活其转录活性［58］。Birsen等［59］研究发现，APR-246能通过耗竭细胞内GSH并增加脂质过氧化物的产生来诱导AML细胞中的铁死亡，导致细胞膜的氧化损伤。此外，天然抗癌化合物萝卜硫素也通过氨基酸代谢途径来诱导白血病细胞铁死亡，其作用于U-937白血病细胞后，可出现GSH耗竭、GPX4表达减低和脂质过氧化增加［60］。
此外，一些药物通过靶向铁代谢途径诱导铁死亡。双氢青蒿素是青蒿素的半合成衍生物之一，能够抑制多种肿瘤生长。有研究发现双氢青蒿素通过调节AMPK/mTOR/p70S6k信号通路诱导自噬，加速铁蛋白降解，增加不稳定铁池，促进细胞中活性氧积累，最终导致AML细胞发生铁死亡［61］。香蒲新甙是天然产物伤寒花粉提取物中的黄酮类化合物，具有多种药理作用。Zhu等［62］研究表明，香蒲新甙可通过促进腺苷一磷酸活化蛋白激酶信号通路的激活而触发AML细胞自噬，最终导致铁蛋白降解、活性氧积累和铁死亡，因此具有抗AML的前景。研究发现，和厚朴酚可以降低AML细胞活性，诱导细胞停滞在G0/G1期，具有抗白血病作用，这是由于和厚朴酚能显著上调细胞内脂质过氧化物和HO-1水平而触发AML细胞铁死亡［63］。
其他药物如奈拉替尼可以通过自噬依赖性铁死亡抑制AML细胞增殖并促进细胞凋亡［64］。总之，铁死亡诱导剂与传统化疗药物的联合使用增强了后者的敏感性，有助于克服耐药，从而提高疾病缓解率，改善预后。但铁死亡诱导剂应用于临床的有效性和安全性还须进一步验证。
lncRNA在体内发挥重要生理作用，不仅通过参与各种信号通路作为致癌基因或肿瘤抑制因子发挥作用，而且还作为各种癌症如AML的预测标志物。既往研究表明，lncRNA在肿瘤发生中参与铁代谢相关的死亡过程［65-66］。Wang等［67］发现LINC00618在白血病中呈低表达，但在长春新碱治疗后高表达；进一步研究发现LINC00618通过增加脂质活性氧和铁的水平、减少SLC7A11表达以及抑制淋巴特异性解旋酶的表达来加速铁死亡，且LINC00618在长春新碱诱导细胞铁死亡和凋亡的过程中发挥重要作用。研究显示，热休克蛋白表达与AML的主要不良预后因素相关［68］。Ge等［69］研究了同时作为AML中热休克蛋白依赖性和铁死亡相关的lncRNA，确定了四种具有预后价值的lncRNA——AL138716.1、AC000120.1、AC004947.1和LINC01547。AML与环状RNA的调节受损也有关。KDM4C基因表达一种新的环状RNA，即circKDM4C，后者在乳腺癌中发挥抑癌基因的作用。Dong等［70］研究表明，circKDM4C通过靶向has-let-7b-5p上调P53表达，从而诱导AML细胞铁死亡。
铁死亡相关基因在AML中的预后意义和功能越来越受到重视。Zhu等［71］比较了AML患者和正常人骨髓组织标本，提出10个与AML患者预后相关的铁死亡基因（其中CD44、DPP4、SAT1和NCOA4上调，CHAC1、CISD1、SLC7A11、AIFM2、G6PD和ACSF2下调），建立了预后风险模型；发现患者对药物的敏感性与铁死亡基因存在相关性。因此，铁死亡相关基因可能可以作为AML治疗新靶点。Fu等［72］通过共识聚类确定了两种具有不同预后和肿瘤免疫微环境的铁死亡相关分子亚型（C1和C2）。C1亚型患者多呈现细胞毒性免疫细胞（如CD8+/中央记忆T细胞、NK细胞和非调节性CD4+ T细胞）浸润增加和抑制性免疫亚群（如M2型巨噬细胞、中性粒细胞和单核细胞）减少，以及良好的临床结果。而C2亚型中S100A8、S100A9、LILRB3、KLF4、LST1和ITGB2等基因上调与白血病细胞存活、增殖和耐药性增加有关。
2.2. 靶向铁死亡可以逆转CML对伊马替尼耐药
CML是一种由费城染色体引起的造血系统恶性肿瘤。甲磺酸伊马替尼是一种小分子酪氨酸激酶抑制剂，广泛用于治疗CML，但部分患者可出现耐药。Liu等［73］研究发现，半胱氨酸缺失可在体外诱导伊马替尼耐药的CML细胞系（K562/G01）发生铁死亡，而对于野生型亲本细胞（K562）无效。这与K562/G01细胞中TXNRD1基因上调有关。TXNRD1是硫氧还蛋白系统的成员，是一种重要的抗氧化剂和氧化还原调节剂。敲低TXNRD1的CML细胞对半胱氨酸耗竭的敏感性增加，表明硫氧还蛋白系统可能在调节铁死亡中发挥作用。此外，因伊马替尼具有心脏毒性，患者在接受治疗过程中易出现心血管并发症。Song等［74］发现铁死亡依赖性途径参与了伊马替尼诱导的心脏毒性：伊马替尼可上调P53表达、下调GPX4表达，通过抑制Nrf2信号通路诱导铁死亡，而这些变化可被铁抑素-1（一种铁死亡抑制剂）逆转。因此，铁死亡或许可成为预防伊马替尼心脏毒性的靶点。
艾蒿具有抗高血压、抗菌和抗炎等药理活性，其提取物还具有抗氧化特性［75］。Zamarioli等［76］研究发现，艾蒿的水醇提取物可通过诱导溶酶体释放钙离子，从而激活CML细胞的铁死亡和坏死性凋亡。然而，该药物诱导CML细胞铁死亡的靶点仍不明确。
无论是否存在伊马替尼耐药，汉防己碱柠檬酸盐对CML均表现出较好的抗肿瘤活性［77］。目前尚未证实铁死亡是CML细胞死亡的主要方式，而在乳腺癌细胞中，有研究发现汉防己碱柠檬酸盐能通过抑制GPX4表达和激活NCOA4介导的铁蛋白自噬诱导肿瘤细胞发生铁死亡［78］。
2.3. 铁死亡可能在MDS细胞死亡过程中发挥重要作用
MDS是一种异质性骨髓恶性肿瘤，其特征是一种或多种细胞谱系发育不良、无效造血以及具有向白血病转化的较高风险［79］。地西他滨是用于治疗相对高危MDS的标准药物之一，一般认为地西他滨主要通过去甲基化治疗MDS。Lv等［80］发现，地西他滨可以通过降低GSH水平和GPX4活性诱导MDS、AML细胞的活性氧水平升高，从而导致铁死亡。铁死亡可能是地西他滨诱导MDS细胞死亡的主要机制。最近，Li等［54］使用Erastin处理MDS细胞系SKM-1发现，Erastin在MDS中可诱导铁死亡，且其与阿扎胞苷在MDS治疗中存在潜在协同作用。此外，Chen等［81］在MDS和健康骨髓标本中鉴定了与铁死亡相关的差异表达基因（BNIP3、MDM2和RRM2），MDS标本中MDM2和RRM2表达量减少，而BNIP3表达量增加，具有诊断和预后意义。富集分析结果表明，氧化应激和免疫反应可能在MDS中发挥至关重要的作用。
2.4. 铁死亡与其他髓系肿瘤
目前，铁死亡在其他髓系肿瘤中的研究很少。JAK2
V617F是一种功能性突变，常见于MPN或克隆性造血的老年患者，与动脉粥样硬化血栓性疾病的风险增加相关［82］。Liu等［83］构建了一种在红系谱系中表达JAK2
V617F的小鼠——VFEpoR小鼠，铁死亡、脂质过氧化和动脉粥样硬化程度在VFEpoR小鼠中增加。该研究显示，VFEpoR小鼠红细胞的抗氧化防御能力降低，脂质氢过氧化物增加；而铁死亡抑制剂Liproxstatin-1可有效逆转上述反应。这不仅提示冠状动脉粥样硬化患者有可能受益于铁死亡抑制剂，同时MPN与铁死亡之间的关系也值得进一步研究。
3. 靶向铁死亡的抗髓系肿瘤药物机制
铁死亡主要通过氨基酸代谢途径、脂质代谢途径和铁代谢途径进行调节［84-86］。近年来，研究发现多种药物可以通过这些途径靶向铁死亡杀伤髓系肿瘤细胞，见图1。
图1. 靶向铁死亡的抗髓系肿瘤作用及其分子机制.
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调控铁死亡的三个经典途径包括氨基酸代谢途径、脂质代谢途径和铁代谢途径，其他非经典途径包括GCH1-BH4系统、FSP1-泛醇系统和DHODH-泛醇系统. 不同铁死亡诱导剂在髓系肿瘤中作用靶点不同，如Erastin、索拉非尼和柳氮磺吡啶抑制Xc-系统，APR-246、萝卜硫素和地西他滨对GSH产生耗竭作用，RSL3、FIN56和FINO2抑制GPX4；双氢青蒿素和香蒲新甙促进铁蛋白降解，和厚朴酚上调HO-1水平. SLC7A11：溶质载体家族7成员11；SLC3A2：溶质载体家族3成员2；GPX：谷胱甘肽过氧化物酶；NADPH：还原型烟酰胺腺嘌呤二核苷酸磷酸；NADP+：烟酰胺腺嘌呤二核苷酸磷酸（氧化态）；GSSG：氧化型谷胱甘肽；PL-OH：磷脂醇；PL-OOH：磷脂过氧化物；GCH：GTP环化水解酶；GTP：鸟苷三磷酸；DHODH：二氢乳清酸脱氢酶；PUFA：多不饱和脂肪酸；ACSL：酰基辅酶A合成酶长链家族；CoA：辅酶A；LPCAT：溶血磷脂酰胆碱酰基转移酶；KEAP：Kelch样环氧氯丙烷相关蛋白；Nrf：核转录因子红系2相关因子；FSP：铁死亡抑制蛋白；HEPH：膜铁转运辅助蛋白；CP：血浆铜蓝蛋白；STEAP：前列腺六跨膜上皮抗原；DMT：二价金属离子转运体；HO：血红素加氧酶；PCBP：多聚胞嘧啶结合蛋白；NCOA：核受体共激活因子.
3.1. 作用于氨基酸代谢途径
在氨基酸代谢途径中，SLC7A11-GSH-GPX4系统通过协助胱氨酸转入细胞，介导GSH合成，从而产生清除脂质过氧化物的作用［86-87］。在AML中，Erastin、索拉非尼和柳氮磺吡啶以SLC7A11为靶点［54-56］，APR-26靶向TP53［59］，萝卜硫素通过耗竭GSH和抑制GPX4，对氨基酸代谢通路产生抑制作用［60］，从而促进铁死亡。在MDS中，Erastin和地西他滨也通过铁死亡的氨基酸代谢途径对肿瘤产生杀伤作用［54， 80］。
3.2. 作用于脂质代谢途径
在脂质代谢途径中，PUFA通过ACSL4与辅酶A结合，再通过溶血磷脂酰胆碱酰基转移酶3进行额外修饰，生成PUFA-PL复合物［88］。然后，这些复合物可以被ALOX催化，产生PUFA-磷脂过氧化物，并最终导致产生脂质过氧化物，促进铁死亡［89］。与PUFA不同，单不饱和脂肪酸由ACSL3激活，具有抗氧化和抑制PUFA-PL过氧化的作用，可以抑制铁死亡［90］。ALOX抑制剂、ACSL4抑制剂（如噻唑烷二酮）、维生素E类似物、铁抑素和脂氧素等通过抑制脂质代谢途径对铁死亡产生抑制作用［91］。但目前在髓系肿瘤中仍无靶向该途径的药物。
3.3. 作用于铁代谢途径
铁在促进肿瘤细胞增殖、侵袭和代谢方面发挥着至关重要的作用。细胞内铁可以通过芬顿反应产生羟基自由基，促进脂质过氧化，破坏细胞膜，最终诱导铁死亡［84，92］。细胞内过量铁储存于FTH中，保护细胞免于铁死亡［93］。铁蛋白自噬（一种NCOA4介导的溶酶体中铁蛋白的自噬降解）通过增加从铁蛋白中释放游离铁来诱导铁死亡［94］。HO-1由BAY 11-7085（一种IκBα磷酸化抑制剂）通过细胞内氧化还原调节和铁积累介导铁死亡［95］。双氢青蒿素和香蒲新甙通过促进铁蛋白自噬来促进AML细胞铁死亡，而和厚朴酚以HO-1作为靶点导致AML细胞铁死亡。
4. 结语
铁参与机体多种细胞基本生物过程，影响克隆性髓系疾病的病程、肿瘤微环境以及感染免疫的发生和防御。因此，控制铁稳态至关重要。本文阐述了髓系肿瘤与正常状态的铁代谢差异，以及靶向铁代谢的治疗策略。铁超载标志物在髓系肿瘤AML和MDS中具有预后相关性。但铁超载标志物易受炎症等多方面因素的影响，这也是其作为预后标志物的局限。将铁代谢作为MDS和AML的可能靶点的治疗策略可基于以下四种途径：通过铁螯合减少细胞功能所需的铁、调节参与铁代谢的蛋白质、诱导铁死亡和利用铁相关蛋白进行靶向药物递送［2］。目前，大多数研究均为针对铁螯合剂的使用，其他方法仍处于研发的早期阶段。
近年，越来越多的学者认可铁死亡是一种程序性细胞死亡，其在恶性肿瘤中的潜在治疗靶点已成为肿瘤研究领域的热点。大量研究显示，铁死亡在AML中具有抗白血病的作用，且许多药物和天然产物（如柳氮磺吡啶、索拉非尼、双氢青蒿素和萝卜硫素等）具有杀伤AML细胞的铁死亡相关机制，为AML治疗提供了新的选择。目前，铁死亡在其他类型的髓系肿瘤中研究相对较少。此外，研发与铁死亡相关的新靶标，并将其与现有细胞毒药物联合应用，可能会增强单一药物的疗效，对克服髓系肿瘤耐药和改善预后具有潜在重要临床转化意义。
虽然髓系肿瘤中靶向铁代谢和铁死亡的临床应用前景可期，但未来仍有很长的道路需要探索，如哪些患者更加适合铁死亡诱导剂的治疗？毋庸置疑，今后需要更多的多中心临床试验验证并明确铁代谢及铁死亡靶向药物的疗效和不良反应的耐受性，以及如何与其他抗白血病药物联合以克服耐药等关键科学问题；阐明如何运用铁死亡诱导剂更加精准地靶向髓系肿瘤细胞发生铁死亡的同时规避其对机体正常组织器官功能的损害？这些问题的答案有待于髓系肿瘤中铁代谢和铁死亡相关的分子机制研究不断深入，相信这对于未来开发有效的抗癌药物和改善患者预后具有重大意义。
Acknowledgments
研究得到浙江省自然科学基金（LBY23H080002）、浙江省医药卫生科技计划（2023KY348）、浙江省卫生高层次人才（浙卫办〔2022〕32号）支持
Acknowledgments
This work was supported by the Natural Science Foundation of Zhejiang Province (LBY23H 080002), Medical and Health Science and Technology Plan of Zhejiang Province (2023KY348), Health High level Talents of Zhejiang Province (Zhejiang Health Office 〔2022〕 No. 32)
［缩略语］
急性髓系白血病（acute myeloid leukemia，AML）；骨髓增生性肿瘤（myeloproliferative neoplasms，MPN）；慢性髓系白血病（chronic myeloid leukemia，CML）；真性红细胞增多症（polycythemia vera，PV）；原发性血小板增多症（essential thrombocythemia，ET）；原发性骨髓纤维化（primary myelofibrosis，PMF）；骨髓增生异常综合征（myelodysplastic syndrome，MDS）；转铁蛋白受体（transferrin receptor，TFR）；铁蛋白重链（ferritin heavy chain，FTH）；谷胱甘肽（glutathione，GSH）；转铁蛋白饱和度（transferrin saturation，TSAT）；核受体共激活因子（nuclear receptor coactivator，NCOA）；剪接因子3B亚基1（splicing factor 3B， subunit 1，SF3B1）；ABC转运蛋白亚家族B（ATP-binding cassette subfamily B，ABCB）；跨膜蛋白14C（trans-membrane protein 14C，TMEM14C）；赤铁酮（erythroferrone，ERFE）；附加性梳样蛋白（additional sex combs-like，ASXL）；信号转导及转录活化因子（signal transducer and activator of transcription，STAT）；轻链溶质载体家族7成员11（solute carrier family 7 member 11，SLC7A11）；谷胱甘肽过氧化物酶（glutathione peroxidase，GPX）；血红素加氧酶（heme oxygenase，HO）；长链非编码RNA（long noncoding RNA，lncRNA）；硫氧还蛋白还原酶（thioredoxin reductase，TXNRD）；核转录因子红系2相关因子（nuclear factor-erythroid 2-related factor，Nrf）；多不饱和脂肪酸（polyunsatu-rated fatty acid，PUFA）；酰基辅酶A合成酶长链家族（acyl-CoA synthetase long-chain family，ACSL）；PUFA-磷脂（PUFA-phospholipid，PUFA-PL）；花生四烯酸脂氧合酶（arachidonate lipoxygenase，ALOX）
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所有作者均声明不存在利益冲突
Conflict of Interests
The authors declare that there is no conflict of interests
医学伦理声明
研究不涉及人体或动物实验
Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors
参考文献（References）
1.FARIA C, TZANKOV A. Progression in myeloid neo-plasms: beyond the myeloblast[J]. Pathobiology, 2024, 91(1): 55-75. 10.1159/000530940
[DOI] [PMC free article] [PubMed] [Google Scholar]
2.WEBER S, PARMON A, KURRLE N, et al.
The clinical significance of iron overload and iron metabolism in myelodysplastic syndrome and acute myeloid leukemia[J]. Front Immunol, 2020, 11: 627662. 10.3389/fimmu.2020.627662
[DOI] [PMC free article] [PubMed] [Google Scholar]
3.ROEMHILD K, VON MALTZAHN F, WEISKIRCHEN R, et al.
Iron metabolism: pathophysiology and phar-macology[J]. Trends Pharmacol Sci, 2021, 42(8): 640-656. 10.1016/j.tips.2021.05.001
[DOI] [PMC free article] [PubMed] [Google Scholar]
4.SILVA B, FAUSTINO P. An overview of molecular basis of iron metabolism regulation and the associated pathologies[J]. Biochim Biophys Acta, 2015, 1852(7): 1347-1359. 10.1016/j.bbadis.2015.03.011
[DOI] [PubMed] [Google Scholar]
5.AIGNER E, WEISS G, DATZ C. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver[J]. World J Hepatol, 2015, 7(2): 177-188. 10.4254/wjh.v7.i2.177
[DOI] [PMC free article] [PubMed] [Google Scholar]
6.BOGDAN A R, MIYAZAWA M, HASHIMOTO K, et al.
Regulators of iron homeostasis: new players in metabo-lism, cell death, and disease[J]. Trends Biochem Sci, 2016, 41(3): 274-286. 10.1016/j.tibs.2015.11.012
[DOI] [PMC free article] [PubMed] [Google Scholar]
7.GANZ T. Hepcidin—a regulator of intestinal iron ab-sorption and iron recycling by macrophages[J]. Best Pract Res Clin Haematol, 2005, 18(2): 171-182. 10.1016/j.beha.2004.08.020
[DOI] [PubMed] [Google Scholar]
8.NEMETH E, TUTTLE M S, POWELSON J, et al.
Hep-cidin regulates cellular iron efflux by binding to ferro-portin and inducing its internalization[J]. Science, 2004, 306(5704): 2090-2093. 10.1126/science.1104742
[DOI] [PubMed] [Google Scholar]
9.MUCKENTHALER M U, RIVELLA S, HENTZE M W, et al.
A red carpet for iron metabolism[J]. Cell, 2017, 168(3): 344-361. 10.1016/j.cell.2016.12.034
[DOI] [PMC free article] [PubMed] [Google Scholar]
10.MAIMAITIZUNONG R, WANG K, LI H. Ferroptosis and its emerging role in esophageal cancer[J]. Front Mol Biosci, 2022, 9: 1027912. 10.3389/fmolb.2022.1027912
[DOI] [PMC free article] [PubMed] [Google Scholar]
11.LYU T, LI X, SONG Y. Ferroptosis in acute leukemia[J]. Chin Med J (Engl), 2023, 136(8): 886-898.
[DOI] [PMC free article] [PubMed] [Google Scholar]
12.WANG F, LV H, ZHAO B, et al.
Iron and leukemia: new insights for future treatments[J]. J Exp Clin Cancer Res, 2019, 38(1): 406. 10.1186/s13046-019-1397-3
[DOI] [PMC free article] [PubMed] [Google Scholar]
13.CALLENS C, COULON S, NAUDIN J, et al.
Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia[J]. J Exp Med, 2010, 207(4): 731-750. 10.1084/jem.20091488
[DOI] [PMC free article] [PubMed] [Google Scholar]
14.YANG F, CUI X, WANG H, et al.
Iron overload promotes the progression of MLL-AF9 induced acute myeloid leukemia by upregulation of FOS[J]. Cancer Lett, 2024, 583: 216652. 10.1016/j.canlet.2024.216652
[DOI] [PubMed] [Google Scholar]
15.HOLE P S, ZABKIEWICZ J, MUNJE C, et al.
Overpro-duction of NOX-derived ROS in AML promotes pro-liferation and is associated with defective oxidative stress signaling[J]. Blood, 2013, 122(19): 3322-3330. 10.1182/blood-2013-04-491944
[DOI] [PubMed] [Google Scholar]
16.LOPES M, DUARTE T L, TELES M J, et al.
Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications[J]. Blood Adv, 2021, 5(16): 3102-3112. 10.1182/bloodadvances.2021004373
[DOI] [PMC free article] [PubMed] [Google Scholar]
17.BERTOLI S, PAUBELLE E, BÉRARD E, et al.
Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia[J]. Eur J Haematol, 2019, 102(2): 131-142. 10.1111/ejh.13183
[DOI] [PubMed] [Google Scholar]
18.YI W, ZHANG J, HUANG Y, et al.
Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells[J]. Leukemia, 2024, 38(5): 1003-1018. 10.1038/s41375-024-02169-y
[DOI] [PubMed] [Google Scholar]
19.WANG S, HE X, WU Q, et al.
Transferrin receptor 1-mediated iron uptake plays an essential role in hema-topoiesis[J]. Haematologica, 2020, 105(8): 2071-2082. 10.3324/haematol.2019.224899
[DOI] [PMC free article] [PubMed] [Google Scholar]
20.LIU Q, WANG M, HU Y, et al.
Significance of CD71 expression by flow cytometry in diagnosis of acute leukemia[J]. Leuk Lymphoma, 2014, 55(4): 892-898. 10.3109/10428194.2013.819100
[DOI] [PubMed] [Google Scholar]
21.NAKAMAKI T, KAWABATA H, SAITO B, et al.
Ele-vated levels of transferrin receptor 2 mRNA, not trans-ferrin receptor 1 mRNA, are associated with increased survival in acute myeloid leukaemia[J]. Br J Haematol, 2004, 125(1): 42-49. 10.1111/j.1365-2141.2004.04866.x
[DOI] [PubMed] [Google Scholar]
22.KAWABATA H, NAKAMAKI T, IKONOMI P, et al.
Expression of transferrin receptor 2 in normal and neo-plastic hematopoietic cells[J]. Blood, 2001, 98(9): 2714-2719. 10.1182/blood.v98.9.2714
[DOI] [PubMed] [Google Scholar]
23.GASPARETTO M, PEI S, MINHAJUDDIN M, et al.
Low ferroportin expression in AML is correlated with good risk cytogenetics, improved outcomes and increased sensitivity to chemotherapy[J]. Leuk Res, 2019, 80: 1-10. 10.1016/j.leukres.2019.02.011
[DOI] [PubMed] [Google Scholar]
24.LARRUE C, MOUCHE S, ANGELINO P, et al.
Tar-geting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models[J]. Sci Transl Med, 2024, 16(757): eadk1731. 10.1126/scitranslmed.adk1731
[DOI] [PubMed] [Google Scholar]
25.MORENO BERGGREN D, FOLKVALJON Y, ENGVALL M, et al.
Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register[J]. Br J Haematol, 2018, 181(5): 614-627. 10.1111/bjh.15243
[DOI] [PubMed] [Google Scholar]
26.AWIDI A, ALZU’BI M, ODEH N, et al.
Myelodys-plastic syndromes and myelodysplastic syndromes/myeloproliferative neoplasms: a real-world experience from a developing country[J/OL]. JCO Glob Oncol, 2024, 10: e2300281. 10.1200/go.23.00281 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.PILEGGI C, DI SANZO M, MASCARO V, et al.
Role of serum ferritin level on overall survival in patients with myelodysplastic syndromes: results of a meta-analysis of observational studies[J/OL]. PLoS One, 2017, 12(6): e0179016. 10.1371/journal.pone.0179016
[DOI] [PMC free article] [PubMed] [Google Scholar]
28.DELFORGE M, SELLESLAG D, BEGUIN Y, et al.
Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes[J]. Leuk Res, 2014, 38(5): 557-563. 10.1016/j.leukres.2014.02.003
[DOI] [PubMed] [Google Scholar]
29.CREMERS E, DE WITTE T, DE WREEDE L, et al.
A prospective non-interventional study on the impact of transfusion burden and related iron toxicity on outcome in myelodysplastic syndromes undergoing allogeneic hematopoietic cell transplantation[J]. Leuk Lymphoma, 2019, 60(10): 2404-2414. 10.1080/10428194.2019.1594215
[DOI] [PubMed] [Google Scholar]
30.PETZER V, THEURL I, WEISS G, et al.
EnvIRONmental aspects in myelodysplastic syndrome[J]. Int J Mol Sci, 2021, 22(10): 5202. 10.3390/ijms22105202
[DOI] [PMC free article] [PubMed] [Google Scholar]
31.WERMKE M, ECKOLDT J, GÖTZE K S, et al.
En-hanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after alloge-neic haemopoietic cell transplantation (ALLIVE): a pro-spective, multicentre, observational trial[J/OL]. Lancet Haematol, 2018, 5(5): e201-e210. 10.1016/s2352-3026(18)30036-x
[DOI] [PubMed] [Google Scholar]
32.DE SWART L, SMITH A, JOHNSTON T W, et al.
Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodys-plastic syndromes: a report from the prospective Euro-pean LeukaemiaNet MDS (EUMDS) registry[J]. Br J Haematol, 2015, 170(3): 372-383. 10.1111/bjh.13450
[DOI] [PubMed] [Google Scholar]
33.HOEKS M, BAGGULEY T, VAN MARREWIJK C, et al.
Toxic iron species in lower-risk myelodysplastic syn-drome patients: course of disease and effects on outcome[J]. Leukemia, 2021, 35(6): 1745-1750.
[DOI] [PMC free article] [PubMed] [Google Scholar]
34.RASSOOL F V, GAYMES T J, OMIDVAR N, et al.
Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia?[J]. Cancer Res, 2007, 67(18): 8762-8771. 10.1158/0008-5472.can-06-4807
[DOI] [PubMed] [Google Scholar]
35.SANTINI V, GIRELLI D, SANNA A, et al.
Hepcidin levels and their determinants in different types of myelodysplastic syndromes[J/OL]. PLoS One, 2011, 6(8): e23109. 10.1371/journal.pone.0023109
[DOI] [PMC free article] [PubMed] [Google Scholar]
36.SŁOMKA A, POKRZYWA A, STRZAŁA D, et al.
The role of hepcidin in myelodysplastic syndromes (MDS): a systematic review of observational studies[J]. Cancers (Basel), 2024, 16(2): 332. 10.3390/cancers16020332
[DOI] [PMC free article] [PubMed] [Google Scholar]
37.GU S, CHANG C, ZHAO Y, et al.
Decitabine treatment could ameliorate primary ironoverload in myelodys-plastic syndrome patients[J]. Cancer Invest, 2015, 33(4): 98-106. 10.3109/07357907.2014.1001895
[DOI] [PubMed] [Google Scholar]
38.YOSHIDA K, SANADA M, SHIRAISHI Y, et al.
Fre-quent pathway mutations of splicing machinery in myelo-dysplasia[J]. Nature, 2011, 478(7367): 64-69. 10.1038/nature10496
[DOI] [PubMed] [Google Scholar]
39.CLOUGH C A, PANGALLO J, SARCHI M, et al.
Coor-dinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelo-dysplastic syndrome[J]. Blood, 2022, 139(13): 2038-2049. 10.1182/blood.2021012652
[DOI] [PMC free article] [PubMed] [Google Scholar]
40.BONDU S, ALARY A S, LEFÈVRE C, et al.
A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome[J]. Sci Transl Med, 2019, 11(500): eaav5467. 10.1126/scitranslmed.aav5467
[DOI] [PMC free article] [PubMed] [Google Scholar]
41.HUANG L, LIU Z, LIU H, et al.
Iron overload impairs bone marrow mesenchymal stromal cells from higher-risk MDS patients by regulating the ROS-related Wnt/β-Catenin pathway[J]. Stem Cells Int, 2020, 2020: 8855038. 10.1155/2020/8855038
[DOI] [PMC free article] [PubMed] [Google Scholar]
42.HAFERLACH T, NAGATA Y, GROSSMANN V, et al.
Landscape of genetic lesions in 944 patients with myelo-dysplastic syndromes[J]. Leukemia, 2014, 28(2): 241-247. 10.1038/leu.2013.336
[DOI] [PMC free article] [PubMed] [Google Scholar]
43.RAMPAL R, AL-SHAHROUR F, ABDEL-WAHAB O, et al.
Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myelopro-liferative neoplasm pathogenesis[J/OL]. Blood, 2014, 123(22): e123-133. 10.1182/blood-2014-02-554634
[DOI] [PMC free article] [PubMed] [Google Scholar]
44.ALBAYRAK C, TARKUN P, BIRTAŞ ATEŞOĞLU E, et al.
The role of hepcidin, GDF15, and mitoferrin-1 in iron metabolism of polycythemia vera and essential thrombocytosis patients[J]. Turk J Med Sci, 2019, 49(1): 74-80. 10.3906/sag-1803-13
[DOI] [PMC free article] [PubMed] [Google Scholar]
45.HANDA S, GINZBURG Y, HOFFMAN R, et al.
Hep-cidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis[J]. Curr Opin Hematol, 2023, 30(2): 45-52. 10.1097/moh.0000000000000747
[DOI] [PMC free article] [PubMed] [Google Scholar]
46.MARCHIOLI R, FINAZZI G, SPECCHIA G, et al.
Cardiovascular events and intensity of treatment in polycythemia vera[J]. N Engl J Med, 2013, 368(1): 22-33. 10.1056/nejmoa1208500
[DOI] [PubMed] [Google Scholar]
47.BENNETT C, JACKSON VE, PETTIKIRIARACHCHI A, et al.
Iron homeostasis governs erythroid phenotype in polycythemia vera[J]. Blood, 2023, 141(26): 3199-3214.
[DOI] [PMC free article] [PubMed] [Google Scholar]
48.KREMYANSKAYA M, KUYKENDALL A T, PEMMARAJU N, et al.
Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera[J]. N Engl J Med, 2024, 390(8): 723-735. 10.1056/nejmoa2308809
[DOI] [PubMed] [Google Scholar]
49.PORTER J B, SCRIMGEOUR A, MARTINEZ A, et al.
SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers[J]. Am J Hematol, 2023, 98(9): 1425-1435. 10.1002/ajh.27015
[DOI] [PubMed] [Google Scholar]
50.CHIFOTIDES H T, BOSE P, VERSTOVSEK S. Mome-lotinib: an emerging treatment for myelofibrosis patients with anemia[J]. J Hematol Oncol, 2022, 15(1): 7. 10.1186/s13045-021-01157-4
[DOI] [PMC free article] [PubMed] [Google Scholar]
51.YANG W S, SRIRAMARATNAM R, WELSCH M E, et al.
Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1-2): 317-331. 10.1016/j.cell.2013.12.010
[DOI] [PMC free article] [PubMed] [Google Scholar]
52.DAVER N G, MAITI A, KADIA T M, et al.
TP53-mutated myelodysplastic syndrome and acute myeloid leukemia: biology, current therapy, and future directions[J]. Cancer Discov, 2022, 12(11): 2516-2529. 10.1158/2159-8290.cd-22-0332
[DOI] [PMC free article] [PubMed] [Google Scholar]
53.YU Y, XIE Y, CAO L, et al.
The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents[J/OL]. Mol Cell Oncol, 2015, 2(4): e1054549. 10.1080/23723556.2015.1054549
[DOI] [PMC free article] [PubMed] [Google Scholar]
54.LI J, MA J, ZHANG R, et al.
A new therapeutic per-spective: erastin inhibits tumor progression by driving ferroptosis in myelodysplastic syndromes[J]. J Investig Med, 2024, 72(5): 414-424. 10.1177/10815589241246541 [DOI] [PubMed] [Google Scholar]
55.PARDIEU B, PASANISI J, LING F, et al.
Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia[J]. Leukemia, 2022, 36(6): 1585-1595. 10.1038/s41375-022-01573-6
[DOI] [PubMed] [Google Scholar]
56.DIXON S J, PATEL D N, WELSCH M, et al.
Phar-macological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis[J/OL]. Elife, 2014, 3: e02523. 10.7554/elife.02523 [DOI] [PMC free article] [PubMed] [Google Scholar]
57.LEY T J, MILLER C, DING L, et al.
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia[J]. N Engl J Med, 2013, 368(22): 2059-2074. 10.1056/nejmoa1301689
[DOI] [PMC free article] [PubMed] [Google Scholar]
58.MASLAH N, SALOMAO N, DREVON L, et al.
Syner-gistic effects of PRIMA-1Met (APR-246) and 5-aza-citidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia[J]. Haematologica, 2020, 105(6): 1539-1551. 10.3324/haematol.2019.218453
[DOI] [PMC free article] [PubMed] [Google Scholar]
59.BIRSEN R, LARRUE C, DECROOCQ J, et al.
APR-246 induces early cell death by ferroptosis in acute myeloid leukemia[J]. Haematologica, 2022, 107(2): 403-416. 10.3324/haematol.2020.259531
[DOI] [PMC free article] [PubMed] [Google Scholar]
60.GRECO G, SCHNEKENBURGER M, CATANZARO E, et al.
Discovery of sulforaphane as an inducer of ferroptosis in U-937 leukemia cells: expanding its anticancer potential[J]. Cancers (Basel), 2021, 14(1): 76. 10.3390/cancers14010076
[DOI] [PMC free article] [PubMed] [Google Scholar]
61.DU J, WANG T, LI Y, et al.
DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin[J]. Free Radic Biol Med, 2019, 131: 356-369. 10.1016/j.freeradbiomed.2018.12.011
[DOI] [PubMed] [Google Scholar]
62.ZHU H Y, HUANG Z X, CHEN G Q, et al.
Typhane-oside prevents acute myeloid leukemia (AML) through suppressing proliferation and inducing ferroptosis associated with autophagy[J]. Biochem Biophys Res Commun, 2019, 516(4): 1265-1271. 10.1016/j.bbrc.2019.06.070
[DOI] [PubMed] [Google Scholar]
63.LAI X, SUN Y, ZHANG X, et al.
Honokiol induces ferroptosis by upregulating HMOX1 in acute myeloid leukemia cells[J]. Front Pharmacol, 2022, 13: 897791. 10.3389/fphar.2022.897791
[DOI] [PMC free article] [PubMed] [Google Scholar]
64.MA H, LIU Y, MIAO Z, et al.
Neratinib inhibits pro-liferation and promotes apoptosis of acute myeloid leukemia cells by activating autophagy-dependent fer-roptosis[J]. Drug Dev Res, 2022, 83(7): 1641-1653. 10.1002/ddr.21983
[DOI] [PubMed] [Google Scholar]
65.JIANG N, ZHANG X, GU X, et al.
Progress in under-standing the role of lncRNA in programmed cell death[J]. Cell Death Discov, 2021, 7(1): 30. 10.1038/s41420-021-00407-1
[DOI] [PMC free article] [PubMed] [Google Scholar]
66.DAI C, ZHAO C, XU M, et al.
Serum lncRNAs in early pregnancy as potential biomarkers for the prediction of pregnancy-induced hypertension, including preeclam-psia[J]. Mol Ther Nucleic Acids, 2021, 24: 416-425. 10.1016/j.omtn.2021.03.010
[DOI] [PMC free article] [PubMed] [Google Scholar]
67.WANG Z, CHEN X, LIU N, et al.
A nuclear long non-coding RNA LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis[J]. Mol Ther, 2021, 29(1): 263-274. 10.1016/j.ymthe.2020.09.024
[DOI] [PMC free article] [PubMed] [Google Scholar]
68.THOMAS X, CAMPOS L, MOUNIER C, et al.
Expres-sion of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia[J]. Leukemia Res, 2005, 29(9): 1049-1058. 10.1016/j.leukres.2005.02.010
[DOI] [PubMed] [Google Scholar]
69.GE F, WANG Y, SHARMA A, et al.
Computational analysis of heat shock proteins and ferroptosis-asso-ciated lncRNAs to predict prognosis in acute myeloid leukemia patients[J]. Front Genet, 2023, 14: 1218276. 10.3389/fgene.2023.1218276
[DOI] [PMC free article] [PubMed] [Google Scholar]
70.DONG L H, HUANG J J, ZU P, et al.
CircKDM4C upregulates P53 by sponging hsa-let-7b-5p to induce ferroptosis in acute myeloid leukemia[J]. Environ Toxicol, 2021, 36(7): 1288-1302. 10.1002/tox.23126
[DOI] [PubMed] [Google Scholar]
71.ZHU K, LANG Z, ZHAN Y, et al.
A novel 10-gene ferroptosis-related prognostic signature in acute myeloid leukemia[J]. Front Oncol, 2022, 12: 1023040. 10.3389/fonc.2022.1023040
[DOI] [PMC free article] [PubMed] [Google Scholar]
72.FU D, ZHANG B, WU S, et al.
Molecular subtyping of acute myeloid leukemia through ferroptosis signatures predicts prognosis and deciphers the immune micro-environment[J]. Front Cell Dev Biol, 2023, 11: 1207642. 10.3389/fcell.2023.1207642
[DOI] [PMC free article] [PubMed] [Google Scholar]
73.LIU S, WU W, CHEN Q, et al.
TXNRD1: a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro [J]. Oxid Med Cell Longev, 2021, 2021: 7674565. 10.1155/2021/7674565
[DOI] [PMC free article] [PubMed] [Google Scholar]
74.SONG C, LI D, ZHANG J, et al.
Role of ferroptosis in promoting cardiotoxicity induced by imatinib mesylate via down-regulating Nrf2 pathways in vitro and in vivo [J]. Toxicol Appl Pharmacol, 2022, 435: 115852. 10.1016/j.taap.2021.115852
[DOI] [PubMed] [Google Scholar]
75.ANIBOGWU R, JESUS K, PRADHAN S, et al.
Extrac-tion, isolation and characterization of bioactive com-pounds from artemisia and their biological significance: a review[J]. Molecules, 2021, 26(22): 6995. 10.3390/molecules26226995
[DOI] [PMC free article] [PubMed] [Google Scholar]
76.ZAMARIOLI L, SANTOS M, ERUSTES A G, et al.
Artemisia vulgaris induces tumor-selective ferroptosis and necroptosis via lysosomal Ca2+ signaling[J]. Chin J Integr Med, 2024, 30(6): 525-533. 10.1007/s11655-023-3712-2
[DOI] [PubMed] [Google Scholar]
77.XU X H, GAN Y C, XU G B, et al.
Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis[J]. J Zhejiang Univ Sci B, 2012, 13(11): 867-874. 10.1631/jzus.b1200021
[DOI] [PMC free article] [PubMed] [Google Scholar]
78.YIN J, LIN Y, FANG W, et al.
Tetrandrine citrate sup-presses breast cancer via depletion of glutathione per-oxidase 4 and activation of nuclear receptor coactivator 4-mediated ferritinophagy[J]. Front Pharmacol, 2022, 13: 820593. 10.3389/fphar.2022.820593
[DOI] [PMC free article] [PubMed] [Google Scholar]
79.GANGULY B B, BANERJEE D, AGARWAL M B. Impact of chromosome alterations, genetic mutations and clonal hematopoiesis of indeterminate potential (CHIP) on the classification and risk stratification of MDS[J]. Blood Cells Mol Dis, 2018, 69: 90-100. 10.1016/j.bcmd.2017.10.001
[DOI] [PubMed] [Google Scholar]
80.LV Q, NIU H, YUE L, et al.
Abnormal ferroptosis in myelodysplastic syndrome[J]. Front Oncol, 2020, 10: 1656. 10.3389/fonc.2020.01656
[DOI] [PMC free article] [PubMed] [Google Scholar]
81.CHEN X, LI C, WANG Y, et al.
Diagnostic and pro-gnostic value of ferroptosis-related genes in patients with myelodysplastic neoplasms[J]. Hematology, 2023, 28(1): 2288475. 10.1080/16078454.2023.2288475
[DOI] [PubMed] [Google Scholar]
82.WANG W, LIU W, FIDLER T, et al.
Macrophage inflam-mation, erythrophagocytosis, and accelerated athero-sclerosis in Jak2 (V617F) mice[J/OL]. Circ Res, 2018, 123(11): e35-e47. 10.1161/circresaha.118.313283
[DOI] [PMC free article] [PubMed] [Google Scholar]
83.LIU W, ÖSTBERG N, YALCINKAYA M, et al.
Erythroid lineage Jak2V617F expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis[J/OL]. J Clin Invest, 2022, 132(13): e155724. 10.1172/jci155724
[DOI] [PMC free article] [PubMed] [Google Scholar]
84.TANG D, CHEN X, KANG R, et al.
Ferroptosis: molec-ular mechanisms and health implications[J]. Cell Res, 2021, 31(2): 107-125. 10.1038/s41422-020-00441-1
[DOI] [PMC free article] [PubMed] [Google Scholar]
85.RIEGMAN M, SAGIE L, GALED C, et al.
Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture[J]. Nat Cell Biol, 2020, 22(9): 1042-1048. 10.1038/s41556-020-0565-1
[DOI] [PMC free article] [PubMed] [Google Scholar]
86.DIXON S J, LEMBERG K M, LAMPRECHT M R, et al.
Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072. 10.1016/j.cell.2012.03.042
[DOI] [PMC free article] [PubMed] [Google Scholar]
87.MAGTANONG L, DIXON S J. Ferroptosis and brain injury[J]. Dev Neurosci, 2018, 40(5-6): 382-395. 10.1159/000496922
[DOI] [PMC free article] [PubMed] [Google Scholar]
88.YU D, WANG Q, ZHANG Q, et al.
Molecular mecha-nisms of ferroptosis and its antitumor applications in natural products[J]. Acta Biochim Biophys Sin (Shanghai), 2023, 55(9): 1337-1347. 10.3724/abbs.2023120
[DOI] [PMC free article] [PubMed] [Google Scholar]
89.KAGAN V E, MAO G, QU F, et al.
Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nat Chem Biol, 2017, 13(1): 81-90. 10.1038/nchembio.2238
[DOI] [PMC free article] [PubMed] [Google Scholar]
90.MAGTANONG L, KO P J, TO M, et al.
Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state[J]. Cell Chem Biol, 2019, 26(3): 420-432.e9. 10.1016/j.chembiol.2018.11.016
[DOI] [PMC free article] [PubMed] [Google Scholar]
91.ANGELI J, SHAH R, PRATT D A, et al.
Ferroptosis inhibition: mechanisms and opportunities[J]. Trends Pharmacol Sci, 2017, 38(5): 489-498. 10.1016/j.tips.2017.02.005
[DOI] [PubMed] [Google Scholar]
92.SHEN Z, LIU T, LI Y, et al.
Fenton-reaction-accele-ratable magnetic nanoparticles for ferroptosis therapy of orthotopic brain tumors[J]. ACS Nano, 2018, 12(11): 11355-11365. 10.1021/acsnano.8b06201
[DOI] [PubMed] [Google Scholar]
93.FANG X, CAI Z, WANG H, et al.
Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-medi-ated ferroptosis[J]. Circ Res, 2020, 127(4): 486-501. 10.1161/circresaha.120.316509
[DOI] [PubMed] [Google Scholar]
94.HOU W, XIE Y, SONG X, et al.
Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425-1428. 10.1080/15548627.2016.1187366
[DOI] [PMC free article] [PubMed] [Google Scholar]
95.CHANG L C, CHIANG S K, CHEN S E, et al.
Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis[J]. Cancer Lett, 2018, 416: 124-137. 10.1016/j.canlet.2017.12.025
[DOI] [PubMed] [Google Scholar]