铁死亡在妊娠相关疾病中的研究进展
Research Progress of Ferroptosis in Pregnancy-Related Diseases
DOI: 10.12677/hjbm.2025.152035, PDF, HTML, XML,   
作者: 谢红叶, 陈雪梅：重庆医科大学公共卫生学院卫生毒理教研室，重庆；徐翰婷：重庆医科大学基础医学院组织胚胎学教研室，重庆
关键词: 铁死亡；妊娠相关疾病；RSA；GDM；PE；Ferroptosis； PRD； RSA； GDM； PE
摘要: 铁死亡是一种新发现的程序性细胞死亡形式，其特征是铁过载及脂质过氧化。越来越多的证据表明，铁死亡与妊娠相关疾病的发生密切相关有关，而抑制铁死亡对于妊娠相关疾病的治疗具有一定作用。本综述总结了铁死亡发生的分子机制及铁死亡在妊娠相关疾病中的最新研究进展，期望对妊娠相关疾病的诊治带来新的思路。
Abstract: Ferroptosis is a newly discovered form of programmed cell death characterized by iron overload and lipid peroxidation. Accumulating evidence suggests a significant association between ferroptosis and the pathogenesis of pregnancy-related disorders. Studies have shown that inhibiting ferroptosis may offer therapeutic benefits in managing these conditions. This review aims to elucidate molecular mechanisms underlying ferroptosis and to summarize recent advancements in understanding its role in pregnancy-related diseases, thereby providing novel insights for the diagnosis and treatment of such disorders.
文章引用：谢红叶, 徐翰婷, 陈雪梅. 铁死亡在妊娠相关疾病中的研究进展[J]. 生物医学, 2025, 15(2): 296-303. https://doi.org/10.12677/hjbm.2025.152035

1. 引言

铁死亡(Ferroptosis)是近年来新发现的一种细胞程序性死亡方式，其主要特征为细胞内铁过载，同时蓄积有大量的脂质过氧化物。妊娠相关疾病(pregnancy-related diseases, PRD)是一系列妊娠相关并发症的总称，包括复发性自然流产(recurrent spontaneous abortion, RSA)等所导致的早期妊娠丢失，以及妊娠期糖尿病(gestational diabetes mellitus, GDM)、子痫前期(preeclampsia, PE)等疾病。在这些病理状态下，胎儿发育将受到阻碍，同时还会对母亲的健康造成威胁。目前，关于妊娠相关疾病发病机制和治疗手段的研究尚不完善，仍有待进一步的探索。近年来，越来越多的研究开始关注妊娠相关疾病与铁死亡发生之间的关系，因此本文对铁死亡发生的分子机制及其在妊娠相关疾病发生和发展中的作用进行了综述。

2. 铁死亡概述

早在一百年前，科学家就发现了死亡细胞，并认为机体自发性清除坏死或损伤细胞有利于生物进化，许多生理过程都需要细胞死亡的发生以适应周围环境的变化[1] [2]。随着现代医学的发展，传统的细胞死亡方式已经无法解释新出现的细胞死亡形式。细胞死亡命名委员会在2018年根据死亡细胞的形态学、遗传学和生物化学特征将之命名为细胞凋亡、细胞坏死、细胞自噬、细胞焦亡和细胞铁死亡等[3]。铁死亡的提出有利于促进临床医学研究的发展，同时为临床疾病发病机制的研究提供了新方向。最初学者们发现使用RAS家族小GTP酶Erastin和RSL3作用于RAS突变癌细胞后发生了区别于细胞凋亡的细胞死亡，而使用铁螯合剂能够有效减少这种细胞死亡的发生。这种细胞死亡方式发生时并不会造成细胞膜、细胞核及染色体的异常变化，但会导致线粒体畸变—主要表现为细胞线粒体体积缩小、双层膜密度增加、线粒体嵴减少或消失[4] [5]。同时这种细胞死亡方式的发生还会导致细胞内出现一系列生化反应的改变，将导致细胞内谷胱甘肽(GSH)的耗竭，降低谷胱甘肽过氧化物酶4 (GPX4)的活性，从而导致脂质过氧化物不能被GPX4催化的还原反应代谢，Fe2+以类Fenton方式氧化脂质，产生大量的ROS，造成细胞死亡[5] [6]。2012年Dixon等[4]首次将这种细胞死亡方式命名为铁死亡。从遗传学角度来看，铁死亡是一个由多个基因调控的生物过程，主要涉及细胞内铁代谢、脂质过氧化代谢和抗氧化系统相关基因的改变[7]。

3. 铁死亡的发生机制

3.1. 铁过载

铁过载是脂质过氧化物积累和铁死亡发生所必需的。细胞内铁可通过Fenton反应，即Fe2+催化过氧化氢(H2O2)，产生有毒的羟基自由基(·OH)，进而与细胞膜、质膜中的多不饱和脂肪酸反应以产生大量脂质ROS，从而引发脂质过氧化，导致细胞发生铁死亡。此外，Fe2+还充当脂氧合酶或脯氨酸羟化酶(负责脂质过氧化和氧稳态)的辅助因子。因此，Fe2+可诱导脂质ROS的产生并间接促进铁死亡。铁代谢，包括铁的摄取、转运和储存等多环节。任意铁代谢环节受到影响都有可能改变细胞对铁死亡的敏感性，甚至直接引发铁死亡。最近的研究发现，转铁蛋白(transferrin, TF)及其细胞膜表面的转铁蛋白受体1 (protein transferrin receptor 1, TFR1)在细胞铁死亡中起着关键作用。正常生理过程中，Fe3+通过与TF结合在循环中进行运输。待Fe3+被运输至相应的部位后，TFR1可介导其向细胞核内体的转运，并在核内体中进一步被金属还原酶STEAP3还原成为Fe2+。还原后的Fe2+在二价金属离子转运蛋白1 (divalent metal transporter 1, DMT1)的作用下释放到胞质内，形成不稳定铁池[8]。这些Fe2+一部分储存在铁蛋白中，主要以铁蛋白轻链(ferritin light chain, FTL)和铁蛋白重链1 (ferritin heavy chain 1, FTH1)形式存在，另一部分则在胞质内被氧化成Fe3+，后与膜铁转运蛋白(ferroportin, FPN)结合由胞浆转出胞外[9]。此外，核受体辅激活因子4 (nuclear receptor coactivator 4, NCOA4)介导的自噬也是细胞内铁循环的重要方式[10]。当上述铁代谢相关蛋白的表达受到影响或功能失调时，细胞内铁离子浓度可因代谢失衡而升高，导致Fe2+介导的毒性ROS物质产生增加，即可诱发铁死亡。

3.2. 脂质过氧化

哺乳动物的脂质双层由高达62%的不饱和脂肪酸组成，其中35%是多不饱和脂肪酸(PUFA) [11]。然而细胞膜中PUFA的存在是一把双刃剑。一方面，PUFA是细胞膜维持其流动性所必需的[12]，也是细胞能量来源不足时的重要能量来源[13]。另一方面，PUFA，尤其是花生四烯酸(AA)和肾上腺酸(AdA)，在各种生理病理背景下皆可促进脂质过氧化的发生[14]。酰基辅酶A合成酶长链家族成员4 (ACSL4) [15]和溶血磷脂酰胆碱酰基转移酶3 (LPCAT3) [16]与AA/AdA的脂质过氧化反应密切相关。ACSL4首先催化CoA与游离的AA/AdA结合形成AA/AdA-CoA衍生物[17]。然后，AA/AdA-CoA在LPCAT3作用下酯化成磷脂酰乙醇胺(PE)，形成花生四烯酸–磷脂酰乙醇胺(AA/AdA-PE) [16]。最后，这些AA/AdA-PE通过非酶促自氧化[4]或酶介导途径[18]发生过氧化转变为有毒的磷脂氢过氧化物(PE-AA/AdA-OOH)。

磷脂(phospholipid, PL)的非酶促自氧化是一种铁依赖的脂质过氧化过程，由Fe2+和H2O2相互作用(芬顿反应)产生的羟基自由基从脂质中夺取氢原子形成脂质自由基(L•) [19]。之后，脂质自由基与O2结合形成脂质过氧化物自由基(LOO•)，该自由基随后与相邻的PUFA相互作用形成脂质氢过氧化物(LOOH)以及许多亲电物质，例如丙二醛(MDA)和4-羟基壬烯醛(4-HNE) [20] [21]。

脂质过氧化还发生在酶介导的过程中。脂氧合酶(lipoxygenases, LOXs)是一种含有非血红素铁的双加氧酶，在人类中有六种亚型：15-LOX-1、15-LOX-2、12-LOX-1、12-LOX-2、E3-LOX和5-LOX [22]。某些LOXs靶向PUFAs直接氧化生物膜上的PUFAs和含PUFA的脂质，提示LOXs也许能够诱导铁死亡。然而，一些研究也显示，LOX15可与伴侣磷脂酰乙醇胺结合蛋白1 (PEBP1)发生结合，从而抵御erastin或RSL3诱导的铁死亡[23]。一些LOXs抑制剂，如齐留通、MK886、PD146176、黄芩素等，通过激活HEK293细胞中LOX的表达可抑制铁死亡的发生[24] [25]。最新的研究表明，其他加氧酶，如NADPH氧化酶(NOXs)和细胞色素P450氧化还原酶(POR)，也参与了铁死亡的调节[26]。使用NOX抑制剂阿扑西宁(Apocynin)和二苯碘铵(diphenyleneiodonium, DPI)处理人神经母细胞瘤细胞可抑制铁死亡的发生。通过对铁死亡敏感的透明细胞肾细胞癌细胞(ccRCC)和对铁死亡抵抗的黑色素瘤细胞系(UACC257)进行CRISPR/Cas9筛选，发现POR可在Erastin或RSL3诱导的铁死亡中发挥正向作用[27]。

3.3. 抗氧化系统失调

Xc−系统-GSH-GPX4轴是经典的抗氧化通路，其异常也是铁死亡的重要诱因之一。GPX4是一种谷胱甘肽(GSH)依赖性硒酶，可作为磷脂氢过氧化物酶将有毒的PE-AA/AdA-OOH还原为相应的无毒磷脂醇(PLOH)，从而抑制铁死亡。GSH作为还原剂，是GPX4脂质修复功能的底物，能降低铁死亡风险。GSH的生物合成以谷氨酸、甘氨酸和半胱氨酸为基础，与其前体胱氨酸和Xc−系统密切相关。Xc−系统是细胞膜上的一个反向转运体，由SLC7A11和SLC3A2组成，以1:1的比例存在协同向外运输谷氨酸，向内运输胱氨酸。研究发现，Erastin通过与SLC7A11结合降低其活性，抑制胱氨酸的输入，从而减少GSH的合成[28]。在NCI-H1299 (人非小细胞肺癌细胞)中，核转录因子2 (Nrf2)可通过上调SLC7A11的表达抑制铁死亡[29]。高钙和高磷酸盐可下调GPX4的表达，诱导铁死亡[30]。在HT-1080 (人成纤维肉瘤细胞)中，铁死亡诱导剂RSL3可与GPX4共价结合，导致脂质过氧化增加[28]。总之，Xc−系统-GSH-GPX4轴对于铁死亡具有重要意义。

4. 铁死亡和妊娠相关疾病

4.1. 铁死亡与复发性自然流产

RSA是指连续两次或两次以上非故意终止妊娠所导致的流产的发生。世界卫生组织估计，1%~5%的育龄期妇女患有RSA [31]。在所有RSA病例中，约有一半的RSA病因尚不清楚。因此，了解RSA的分子机制对于新治疗靶点的开发至关重要。

CDGSH铁硫结构域2 (CISD2)是一种具有(2Fe-2S)簇的铁硫蛋白，在细胞增殖和铁稳态中起着关键作用。CISD2缺乏会破坏细胞内钙平衡和细胞器通讯，增加ROS的产生，破坏细胞功能，从而导致各种病理条件下的细胞死亡。据报道，CISD2可通过减少脂质过氧化来减轻神经元铁死亡[32]。研究发现CISD2的表达在RSA样本中下调，结合免疫学分析和双样本孟德尔随机化分析发现，CISD2可通过作用于铁死亡成为RSA治疗的靶点之一。此外，研究还发现CISD2敲低可显著降低人绒毛膜滋养层细胞(HTR-8/SVneo)和人原绒毛外滋养层(EVT)细胞的活力，促进ROS的产生，同时抑制两种细胞内铁死亡调节因子GPX4和FTH1的表达[33]。上述发现均表明，CISD2可能是RSA发生和进展中的新型铁死亡抑制因子。

胰岛素样生长因子mRNA结合蛋白3 (IGF2BP3)属于mRNA结合蛋白家族，可通过调节靶mRNA的表达水平参与蛋白质表达的调控。越来越多的研究指出IGF2BP3促进了各种疾病中的细胞迁移和侵袭，例如膀胱癌、乳腺癌和肝细胞癌。考虑到滋养层细胞与肿瘤细胞具有相似的生物学行为，Dai等[34]的研究进一步评估了IGF2BP3对滋养层侵袭和迁移的影响。结果发现，IGF2BP3在RSA患者的绒毛组织以及流产动物模型中均下调，而敲除IGF2BP3可抑制滋养层细胞迁移、侵袭和增殖，同时导致GPX4 mRNA的稳定性受损并促进铁死亡，破坏滋养层细胞的正常功能。这些发现表明，IGF2BP3有可能在未来成为RSA患者的治疗靶点之一。

Yes相关蛋白1 (YAP1)对于器官发育具有重要意义，已被发现可在胎盘中表达，对胎盘发育和滋养层再生和分化至关重要。研究发现，与健康对照组相比，RSA患者绒毛组织中YAP1的表达显著降低。敲低YAP1将导致ROS、MDA和Fe2+在滋养层细胞中积累，引起GSH水平降低。同时研究也发现，滋养细胞内YAP1的表达下调也会诱导铁死亡的发生，从而影响滋养层细胞的侵袭过程，这也提示YAP1可能也是RSA发病的潜在关键分子之一[35]。此外，在雌性CBA/J小鼠与雄性DBA/2小鼠交配形成的RSA模型中，发现其着床部位和胎盘组织均出现了细胞的铁死亡，表现为MDA表达增加，GPX4、GSH和SLC7A11表达降低，ACSL4表达增加，而铁死亡抑制剂Fer-1显著抑制RSA模型小鼠的流产率[36]。基于以上结果推测：抑制铁死亡可能是治疗RSA和改善妊娠结局的重要方式之一。

4.2. 铁死亡与妊娠期糖尿病

GDM表现为妇女在妊娠期间出现不同程度的葡萄糖不耐受，是最常见的妊娠并发症之一，发病率为6.6%~45.3% [37]。GDM与短期和长期并发症的发生有关，例如巨大儿、难产、儿童肥胖症、母亲发展为2型糖尿病和心血管疾病等[38] [39]。胰岛素敏感性指对于胰岛素的抵抗程度，是怀孕期间一项重要的衡量代谢功能的指标。GDM中过度的胰岛素抵抗会促进内源性葡萄糖的产生和脂肪储存的分解，从而增加血糖和游离脂肪酸(FFA)的水平。一项研究表明，患有GDM的女性体内甘油三酯(TG)浓度明显更高。体外模型显示，高脂(HL)和高糖(HG)共同处理将显著提高滋养层细胞死亡率。此外，HL和HG可在怀孕大鼠中诱导GDM，导致大鼠胎盘受损，同时造成ACSL4在胎盘组织中高表达[40]。因此，GDM所导致的过量FFA产生可能促进脂质过氧化水平，从而诱导铁死亡的发生。高血糖环境下培养的BeWo细胞GSH水平降低、铁转运受损和脂质过氧化增加提示铁死亡发生[38]。Han等人最近的一项研究中，使用高浓度葡萄糖诱导滋养细胞，发现线粒体氧化应激的关键调节因子Sirtuin 3 (SIRT3)上调，通过促进AMPK-mTOR通路和降低滋养细胞中的GPX4水平来激活自噬依赖性铁死亡[41]。此外，最近的研究表明，HG培养的HTR-8/SVneo细胞中CircHIPK3可通过miR-1278/DNA甲基转移酶1 (DNMT1)控制GPX4 DNA甲基化来促进铁死亡[42]。

4.3. 铁死亡与先兆子痫

PE是一种妊娠期特有的多器官、多系统综合征，其特征是妊娠20周后新发高血压(收缩压 > 140 mmHg或舒张压 > 90 mmHg)和蛋白尿，可能合并其他母体器官发生功能障碍，包括肾脏或肝脏受累、神经系统或血液系统并发症或子宫胎盘功能障碍(如胎儿生长受限或死产) [43]。据报道，PE的发病率为3%~5% [44]，是导致全球孕产妇致死的高发性疾病之一。PE是多因素、多机制致病的疾病，其具体发病机制尚不十分明确，但目前普遍接受的发病机制主要包括：(i) 滋养细胞迁移和侵袭能力不足，导致子宫螺旋动脉重塑功能受损，引起子宫胎盘血管阻力增加，胎盘灌注不良；(ii) 血管生成和抗血管生成因子表达失衡，造成母体血管内皮细胞损伤、炎症反应激活，进一步发展为广泛的全身内皮功能障碍[44]。

越来越多的证据表明，脂质过氧化是PE损伤的主要因素。人胎盘的单细胞转录组学分析表明，与铁死亡相关的LPCAT3和亚精胺/精胺N1-乙酰基转移酶1(SAT1)在滋养层细胞中高度表达[45]。Irwinda R.等人报道，PE患者体内PUFA水平显著升高[46] [47]。在PE大鼠模型中，胎盘中脂质过氧化的最终产物MDA的浓度急剧增加[31]。同样，PE患者血浆和胎盘中的MDA水平显著升高[48]。总而言之，这些研究表明，导致铁死亡的脂质过氧化可能是导致PE发生的重要原因之一。此外，与健康对照组相比，PE患者的胎盘铁含量增加，TFR1和GSH的水平、GPX4活性和血清硒水平显著降低[49]。另一项研究也表明，PE患者的胎盘绒毛组织中FTL的表达下调。在FTL敲低的妊娠大鼠模型中发现，PE的特征性表型(如滋养细胞侵袭受损、迁移功能障碍和螺旋动脉重塑)伴随着铁死亡代谢的改变。此外，研究表明，PE患者滋养细胞内miR-30b-5p的上调可导致SLC7A11和FPN表达下调，进一步导致GSH水平降低和细胞内游离铁增加[31]。而铁死亡抑制剂Fer-1可阻断这种表型并改善滋养细胞侵袭和迁移[50]。以上所有结果表明：铁死亡和PE之间存在很强的相关性，进一步研究二者之间的关系是必要的。

作为铁死亡的主要抑制因子，GPX4对人类滋养层细胞的细胞活力和功能至关重要。GPX4的突变或表达降低可导致人类胎盘功能障碍和PE [51] [52]，而敲除小鼠的GPX4甚至可直接导致胚胎死亡[53]。另一种新发现的铁死亡调节因子是PLA2G6 [54]，它属于磷脂酶A2家族，在人胎盘滋养层细胞中普遍表达。PLA2G6可以水解与铁死亡有关的氢过氧化物磷脂酰乙醇胺(Hp-PE)，从而防止细胞发生铁死亡[55]。在WT和敲除PLA2G6的BeWo细胞中抑制GPX4的表达，发现敲除PLA2G6逆转了GPX4表达抑制对铁死亡的影响。综上所述，铁死亡参与了PE的发生与发展，并提示了PE的潜在治疗靶点。

5. 总结

铁死亡是一种受多环节调节的细胞死亡形式，涉及铁代谢、脂质代谢和抗氧化系统，受多个基因和信号通路的调节。目前研究多基于小鼠模型，但人类妊娠的胎盘结构和代谢需求与小鼠存在显著差异，可结合单细胞测序、脂质组学和代谢组学技术，解析妊娠不同阶段及疾病模型中铁死亡的动态调控网络，明确关键分子的功能特异性。近年来，越来越多的实验研究正在探索铁死亡在妊娠相关疾病中的作用，以期提供新的潜在治疗药物和治疗靶点。同时，确定铁死亡在妊娠相关疾病中的作用及机制也为进一步完善妊娠相关疾病的诊治提供了理论和实践依据，进而促进人类优生优育。

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