Organelle-specific regulation of ferroptosis
铁死亡的细胞器特异性调节

Oxidative damage 氧化损伤

ROS for ferroptosis can be generated from multiple sources, such as the iron-mediated Fenton reaction, mitochondrial electron transport chain (ETC), nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX), and myeloperoxidase (MPO) [12, 26–29]. The accumulation of iron in cells is one of the hallmarks of ferroptosis [30]. Many proteins mediate iron uptake (e.g., transferrin [TF] [31], transferrin receptor [TFRC] [32], and lactotransferrin [LTF] [33]), storage (e.g., ferritin [6, 7]), utilization (e.g., iron-sulfur proteins [34]), distribution (e.g., CDGSH iron–sulfur domain 1 [CISD1] [35]), and export (e.g., solute carrier family 40 member 1 [SLC40A1] [36, 37], prominin 2 [PROM2] [38], and lipocalin 2 [LCN2] [39]), meaning that they affect the sensitivity of cells to ferroptosis (Fig. 1a). However, the dynamic relationship of iron metabolism and different ROS resources in promoting ferroptosis remains poorly investigated [40].
铁死亡的 ROS 可以从多种来源产生，例如铁介导的芬顿反应、线粒体电子传递链 (ETC)、烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶 (NOX) 和髓过氧化物酶 (MPO) [ 12 , 26 – 29 ]。细胞内铁的积累是铁死亡的标志之一[ 30 ]。许多蛋白质介导铁的摄取（例如，转铁蛋白 [TF] [ 31 ]、转铁蛋白受体 [TFRC] [ 32 ] 和乳转铁蛋白 [LTF] [ 33 ]）、储存（例如，铁蛋白 [ 6 , 7 ]）和利用（例如、铁硫蛋白 [ 34 ]）、分布（例如，CDGSH 铁硫结构域 1 [CISD1] [ 35 ]）和输出（例如，溶质载体家族 40 成员 1 [SLC40A1] [ 36 , 37 ]、突出蛋白 2 [PROM2][ 38 ]和脂质运载蛋白2[LCN2][ 39 ]），这意味着它们影响细胞对铁死亡的敏感性（图1a ） 。然而，铁代谢和不同ROS资源在促进铁死亡中的动态关系仍然缺乏研究[ 40 ]。

Although oxidative DNA damage is also conducive to ferroptosis, lipid peroxidation of polyunsaturated fatty acids (PUFAs) plays a major role in driving lytic cell death. Accordingly, CD36-mediated PUFA uptake [41, 42], acetyl-CoA carboxylase (ACAC)-dependent PUFA synthesis [43], or lipophagy-induced PUFA production [8] might facilitate ferroptosis. The production of oxidative metabolites of PUFA requires additional enzymes. Long-chain acyl-CoA synthetases (ACSLs) activate fatty acids by the addition of a coenzyme A (CoA) group and provide substrates for specific metabolic pathways. ACSL4 [44–46] and ACSL1 [47] are essential for arachidonic acid/adrenic acid-mediated and linolenic acid-mediated ferroptosis, respectively. ACSL3 is responsible for the activation of monounsaturated fatty acids (MUFAs), which competitively inhibit PUFA-induced ferroptosis [48]. Later, lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in phospholipid remodeling for ferroptosis [45]. Finally, different members of the lipoxygenase (ALOX) family mediate ferroptosis through the oxygenation of PUFAs in a cell type-dependent manner [21, 49–51]. Alternatively, cytochrome P450 oxidoreductase (POR) transfers electrons to oxygen and then mediates lipid peroxidation during ferroptosis in an ALOX-independent manner [52, 53]. In addition to PUFAs, the production of plasmalogens in peroxisomes can provide substrates for lipid peroxidation during ferroptosis [54]. This complex complementary pathway of lipid metabolism affects the susceptibility to ferroptosis [55]. It is possible, yet remains to be demonstrated, that sophisticated biochemical methods allowing for the identification of distinct lipid peroxidation products will facilitate a sort of “molecular diagnosis” of the etiology of ferroptotic cell death.
尽管氧化性 DNA 损伤也有利于铁死亡，但多不饱和脂肪酸 (PUFA) 的脂质过氧化在驱动裂解细胞死亡中起着主要作用。因此，CD36 介导的 PUFA 摄取 [ 41 , 42 ]、乙酰辅酶 A 羧化酶 (ACAC) 依赖性 PUFA 合成 [ 43 ] 或自噬诱导的 PUFA 产生 [ 8 ] 可能会促进铁死亡。 PUFA 氧化代谢产物的产生需要额外的酶。长链酰基辅酶 A 合成酶 (ACSL) 通过添加辅酶 A (CoA) 基团来激活脂肪酸，并为特定代谢途径提供底物。 ACSL4 [ 44 – 46 ] 和 ACSL1 [ 47 ] 分别对于花生四烯酸/肾上腺酸介导和亚麻酸介导的铁死亡至关重要。 ACSL3 负责激活单不饱和脂肪酸 (MUFA)，从而竞争性抑制 PUFA 诱导的铁死亡 [ 48 ]。后来，溶血磷脂酰胆碱酰基转移酶 3 (LPCAT3) 参与铁死亡的磷脂重塑 [ 45 ]。最后，脂氧合酶 (ALOX) 家族的不同成员通过 PUFA 的氧化以细胞类型依赖性方式介导铁死亡 [ 21 , 49 – 51 ]。或者，细胞色素 P450 氧化还原酶 (POR) 将电子转移给氧，然后在铁死亡过程中以不依赖 ALOX 的方式介导脂质过氧化反应 [ 52 , 53 ]。除了PUFA之外，过氧化物酶体中缩醛磷脂的产生可以为铁死亡过程中的脂质过氧化提供底物[ 54 ]。这种复杂的脂质代谢补充途径影响铁死亡的易感性[ 55 ]。 有可能，但仍有待证明，允许鉴定不同脂质过氧化产物的复杂生化方法将有助于铁死亡细胞死亡病因学的某种“分子诊断”。

Antioxidant defense 抗氧化防御

Tremendous progress has been made in deconvoluting enzymatic and non-enzymatic antioxidant defense systems in ferroptosis [56]. The most characteristic system is the system xc⁻-glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis (Fig. 1b). Many classical ferroptosis inducers (e.g., erastin and RSL3) are inhibitors of this axis. System xc⁻, a glutamate/cystine transporter, consists of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2). System xc⁻ can maintain intracellular GSH content by mediating the uptake of cystine into cells. GSH acts as a cofactor of many antioxidant enzymes, including GPX4. GPX4 requires GSH to reduce phospholipid hydroperoxides (PLOOHs) to nontoxic phospholipid alcohols (PLOHs) [57]. During ferroptosis, the activity or expression of SLC7A11 and GPX4 are regulated on multiple levels. For example, SLC7A11-mediated cystine uptake also promotes GPX4 protein synthesis through the mechanistic target of rapamycin kinase (MTOR) pathway [58]. GPX4 protein can be stabilized by heat shock protein family A (Hsp70) member 5 (HSPA5) [59], but destabilized by heat shock protein 90 (HSP90) in a context-dependent manner [60]. The transcription of SLC7A11 is upregulated or downregulated by nuclear factor erythroid 2-like 2 (NFE2L2, best known as NRF2) [61] or tumor protein p53 (TP53) [62], respectively. The identification of a large number of GPX4 or SLC7A11 binding proteins further exacerbates the complexity of the regulation of this pathway in ferroptosis [63–66].
在铁死亡中去卷积酶促和非酶促抗氧化防御系统方面已经取得了巨大进展[ 56 ]。最有特征的系统是xc ^-谷胱甘肽（GSH）-谷胱甘肽过氧化物酶4（GPX4）轴系统（图1b ）。许多经典的铁死亡诱导剂（例如erastin 和RSL3）是该轴的抑制剂。系统 xc ^-是一种谷氨酸/胱氨酸转运蛋白，由溶质载体家族 7 成员 11 (SLC7A11) 和溶质载体家族 3 成员 2 (SLC3A2) 组成。系统 xc ^-可以通过介导细胞摄取胱氨酸来维持细胞内 GSH 含量。 GSH 是许多抗氧化酶的辅助因子，包括 GPX4。 GPX4 需要 GSH 将磷脂氢过氧化物 (PLOOH) 还原为无毒的磷脂醇 (PLOH) [ 57 ]。在铁死亡期间，SLC7A11 和 GPX4 的活性或表达在多个水平上受到调节。例如，SLC7A11介导的胱氨酸摄取还通过雷帕霉素激酶（MTOR）途径的机制靶标促进GPX4蛋白合成[ 58 ]。 GPX4 蛋白可以被热休克蛋白家族 A (Hsp70) 成员 5 (HSPA5) 稳定化 [ 59 ]，但会被热休克蛋白 90 (HSP90) 以上下文依赖性方式不稳定 [ 60 ]。 SLC7A11 的转录分别受到核因子红细胞 2 样 2（NFE2L2，最著名的 NRF2）[ 61 ] 或肿瘤蛋白 p53（TP53）[ 62 ] 的上调或下调。大量GPX4或SLC7A11结合蛋白的鉴定进一步加剧了铁死亡中该途径调节的复杂性[63-66 ] 。

In addition to GSH, several intracellular antioxidants, such as coenzyme Q10 (CoQ10), tetrahydrobiopterin (BH4), and dopamine, prevent lipid peroxidation during ferroptosis. Mechanically, apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) [67, 68] and dihydroorotate dehydrogenase (DHODH) [69] inhibit ferroptosis through reducing cytosolic and mitochondrial ubiquinone (CoQ10) to generate ubiquinol, respectively. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for the synthesis of BH4, which acts as a radical trapping antioxidant in inhibiting ferroptosis [70, 71]. Dopamine enhances GPX4 protein stability, which in turn limits lipid peroxidation in ferroptosis [72]. Distinct from GPX4, phospholipase A2 group VI (PLA2G6, also known as iPLA2β) averts ferroptosis by hydrolyzing oxidized phosphatidylethanolamine [73, 74]. These findings underscore the notion that an integrated antioxidant system limits ferroptosis caused by excessive oxidative stress.
除 GSH 外，多种细胞内抗氧化剂，如辅酶 Q10 (CoQ10)、四氢生物蝶呤 (BH4) 和多巴胺，可防止铁死亡过程中的脂质过氧化。从机械角度来说，凋亡诱导因子线粒体相关 2 (AIFM2/FSP1) [ 67 , 68 ] 和二氢乳清酸脱氢酶 (DHODH) [ 69 ] 分别通过减少胞质和线粒体泛醌 (CoQ10) 生成泛醇来抑制铁死亡。 GTP 环水解酶 1 (GCH1) 是 BH4 合成的限速酶，BH4 在抑制铁死亡中充当自由基捕获抗氧化剂 [ 70 , 71 ]。多巴胺增强 GPX4 蛋白稳定性，进而限制铁死亡中的脂质过氧化[ 72 ]。与 GPX4 不同，VI 族磷脂酶 A2（PLA2G6，也称为 iPLA2β）通过水解氧化磷脂酰乙醇胺来避免铁死亡 [ 73 , 74 ]。这些发现强调了一个概念，即整合的抗氧化系统可以限制过度氧化应激引起的铁死亡。

Membrane repair or adhesion
膜修复或粘附

Cell membrane disruption induces not only a rapid and massive influx of Ca²⁺ into the cytosol but also an efflux or release of various endogenous proteins, such as high-mobility group box 1 (HMGB1), which is considered as a major pro-inflammatory DAMP [75]. Although the key effectors responsible for the formation of plasma membrane pores have not yet been determined, the activation of Ca²⁺-dependent endosomal sorting complex required for transport-III (ESCRT-III) machinery can promote plasma membrane repair, thereby limiting the occurrence of ferroptosis and the release of pro-inflammatory DAMPs (Fig. 1c) [76–78]. In addition to ferroptosis, ESCRT-III has a conserved function to repair plasma membrane damage in pyroptosis and necroptosis [79, 80]. Additional work is needed to identify whether the membrane repair mechanisms of specific organelles (e.g., mitochondria or lysosomes) are involved in the defense against ferroptosis [81]. Mounting evidence shows that cell-cell contacts confer cell resistance to ferroptosis [28, 82, 83]. In adjacent cells, ferroptosis may propagate in a rapid wave-like propagation [84]. It can be speculated that specific cytoskeleton-related dynamic changes transmit or limit the oxidative damage of plasma membranes at the contact sites between interacting cells. The elucidation of such hypothetical mechanisms will require the development and standardization of spatially resolved assays for the detection of ferroptosis-associated membrane damage.
细胞膜破坏不仅会导致 Ca ²⁺快速大量流入细胞质，还会导致各种内源蛋白的流出或释放，例如高迁移率族蛋白 1 (HMGB1)，它被认为是主要的促炎因子潮湿[ 75 ]。尽管负责质膜孔形成的关键效应器尚未确定，但运输-III（ESCRT-III）机制所需的Ca ²⁺依赖性内体分选复合物的激活可以促进质膜修复，从而限制发生铁死亡和促炎性 DAMP 的释放（图1c ）[ 76 – 78 ]。除了铁死亡之外，ESCRT-III 还具有修复细胞焦亡和坏死性凋亡中质膜损伤的保守功能 [ 79 , 80 ]。需要进行额外的工作来确定特定细胞器（例如线粒体或溶酶体）的膜修复机制是否参与了铁死亡的防御[ 81 ]。越来越多的证据表明，细胞与细胞的接触赋予细胞对铁死亡的抵抗力[28,82,83 ] 。在相邻细胞中，铁死亡可能以快速波状传播的方式传播[ 84 ]。可以推测，特定的细胞骨架相关的动态变化传递或限制相互作用细胞之间接触部位的质膜的氧化损伤。阐明这种假设机制将需要开发和标准化空间分辨测定法，以检测铁死亡相关的膜损伤。

Mitochondria 线粒体

Ferroptotic cells usually exhibit swollen mitochondria, accompanied by a decrease in cristae, dissipation of the mitochondrial membrane potential, as well as an increase in mitochondrial membrane permeability [5], indicating that mitochondrial dysfunction has occurred. However, the role of mitochondria in ferroptosis is controversial. Early study suggests that mitochondria are not required for ferroptosis because when human osteosarcoma 143B cells are depleted of mitochondrial DNA (mtDNA), which are known as ρ° cells, it has no effect on the pro-ferroptotic effects of SLC7A11 inhibitor erastin [5]. It is important to note that cells lacking mtDNA do have mitochondria. Thus, these results are reminiscent of the initially fallacious interpretation of results involving ρ° cells that were fully susceptible to apoptosis induction (“no need for mitochondria in apoptosis”) [85] that were later reinterpreted to mean that the close-to-obligatory contribution of mitochondrial membrane permeabilization to apoptosis does not require mtDNA [86, 87]. Cells that eliminate mitochondria through parkin RBR E3 ubiquitin protein ligase (PRKN)-mediated mitophagy are less sensitive to ferroptosis triggered by cystine starvation or erastin, but are more sensitive to ferroptosis induced by GPX4 inhibitors [26, 88, 89]. Increasing evidence indicates that mitochondria play a significant role in promoting ferroptosis through context-dependent metabolic effects. Altogether, it appears plausible that mitochondrial biogenesis, dynamics, and turnover affect the number and quality of mitochondria, thereby fine-tuning the activity of ferroptosis inducers.
铁死亡细胞通常表现出线粒体肿胀，并伴有嵴减少、线粒体膜电位耗散以及线粒体膜通透性增加[ 5 ]，表明线粒体功能障碍已经发生。然而，线粒体在铁死亡中的作用存在争议。早期研究表明，铁死亡不需要线粒体，因为当人骨肉瘤 143B 细胞耗尽线粒体 DNA (mtDNA)（即 ρ° 细胞）时，它对 SLC7A11 抑制剂erastin 的促铁死亡作用没有影响 [ 5 ] 。值得注意的是，缺乏线粒体 DNA 的细胞确实有线粒体。因此，这些结果让人想起最初对涉及完全易受凋亡诱导影响的ρ°细胞的结果的错误解释（“凋亡中不需要线粒体”）[ 85 ]，后来被重新解释为意味着接近强制性的线粒体膜透化对细胞凋亡的贡献不需要 mtDNA [ 86 , 87 ]。通过parkin RBR E3泛素蛋白连接酶（PRKN）介导的线粒体自噬消除线粒体的细胞对胱氨酸饥饿或erastin引发的铁死亡不太敏感，但对GPX4抑制剂诱导的铁死亡更敏感[ 26,88,89 ]。越来越多的证据表明，线粒体通过背景依赖性代谢效应在促进铁死亡中发挥着重要作用。总而言之，线粒体的生物发生、动力学和周转会影响线粒体的数量和质量，从而微调铁死亡诱导物的活性，这似乎是合理的。

Lysosomes 溶酶体

Lysosomes are acidic membrane-bound organelles that contribute to ferroptosis through three mechanisms: (i) the activation of autophagy, (ii) the release of lysosomal cathepsins, and (iii) the accumulation of lysosomal iron or nitric oxide.
溶酶体是酸性膜结合细胞器，通过三种机制导致铁死亡：（i）自噬的激活，（ii）溶酶体组织蛋白酶的释放，以及（iii）溶酶体铁或一氧化氮的积累。

Macroautophagy (to which we refer as ‘autophagy’) is a lysosome-dependent degradation pathway characterized by the formation of double-membrane bound vesicles called autophagosomes, which are hierarchically executed by the sequential contribution of autophagy-related (ATG) proteins [129]. The knockdown of ATG genes, such as ATG3, ATG5, ATG7, ATG13, BECN1 (also known as ATG6), and microtubule-associated protein 1 light chain 3 B (MAP1LC3B, also known as ATG8), inhibits ferroptosis in many cancer cells [6, 7, 130]. However, the knockdown of ATG2A promotes ferroptosis in human cervical cancer Hela cells by increasing Fe²⁺ uptake [131]. Several selective autophagy pathways promote ferroptosis by removing different cargoes (Fig. 3a). First, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy [6, 7] and the sequestosome 1 (SQSTM1/p62)-mediated autophagic degradation of SLC40A1 [37] promote ferroptosis by increasing intracellular Fe²⁺ levels. Second, the lipophagy-dependent degradation of LDs increases free fatty acid supplies for subsequent lipid peroxidation during ferroptosis [8]. Third, the SQSTM1-mediated autophagic degradation of aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1), a process known as clockophagy, facilitates ferroptosis induction through increasing intracellular levels of PUFA [132]. Fourth, chaperone-mediated autophagy (CMA) facilitates GPX4 degradation, resulting in an increase in lipid peroxidation that favors ferroptosis [60]. This process is further enhanced by the activation of sphingomyelin phosphodiesterase 1 (SMPD1, also known as ASM), a lysosomal enzyme that plays a major role in sphingolipid metabolism [133]. Although these data support the notion that ferroptosis is an autophagy-dependent form of cell death, the specific pathways used only for this process remain to be characterized [134, 135]. In particular, the question arises whether there would be some kind of specificity in the mechanism of selective autophagy and lipid metabolism that favor ferroptosis [136, 137].
巨自噬（我们称之为“自噬”）是一种溶酶体依赖性降解途径，其特征是形成称为自噬体的双膜结合囊泡，这些囊泡通过自噬相关（ATG）蛋白的顺序贡献分层执行[ 129 ] 。 ATG 基因（例如 ATG3、ATG5、ATG7、ATG13、BECN1（也称为 ATG6）和微管相关蛋白 1 轻链 3 B（MAP1LC3B，也称为 ATG8））的敲除可抑制许多癌细胞中的铁死亡。 6、7、130 ] 。然而，ATG2A 的敲低通过增加 Fe ^{2+ 的}摄取而促进人宫颈癌 Hela 细胞的铁死亡[ 131 ]。几种选择性自噬途径通过去除不同的货物来促进铁死亡（图3a ）。首先，核受体共激活剂 4 (NCOA4) 介导的铁蛋白自噬 [ 6 , 7 ] 和多螯体 1 (SQSTM1/p62) 介导的 SLC40A1 自噬降解 [ 37 ] 通过增加细胞内 Fe ²⁺水平来促进铁死亡。其次，LDs 的自噬依赖性降解增加了铁死亡过程中随后脂质过氧化的游离脂肪酸供应[ 8 ]。第三，SQSTM1介导的芳基碳氢化合物受体核转运蛋白样（ARNTL/BMAL1）的自噬降解，这一过程被称为时钟自噬，通过增加细胞内PUFA的水平促进铁死亡诱导[ 132 ]。第四，分子伴侣介导的自噬（CMA）促进 GPX4 降解，导致脂质过氧化增加，有利于铁死亡 [ 60 ]。 鞘磷脂磷酸二酯酶 1（SMPD1，也称为 ASM）的激活进一步增强了这一过程，鞘磷脂磷酸二酯酶 1 是一种在鞘脂代谢中起主要作用的溶酶体酶 [ 133 ]。尽管这些数据支持铁死亡是一种自噬依赖性细胞死亡形式的观点，但仅用于该过程的具体途径仍有待表征[ 134 , 135 ]。特别是，出现的问题是选择性自噬和脂质代谢机制是否存在某种有利于铁死亡的特异性[ 136 , 137 ]。

An increased lysosomal membrane potential is the initial signal of lysosome-dependent cell death driven by various cell death stimulations. Recently, the release of lysosomal cathepsins, especially cathepsin B (CTSB), has been considered to be contributing to ferroptosis (Fig. 3b). The activation of signal transducer and activator of transcription 3 (STAT3) is required for the upregulation and subsequent lysosomal release of CTSB [138]. CTSB mediates ferroptosis through at least two potential mechanisms. First, CTSB translocates from lysosomes to the nucleus, causing DNA damage and subsequent STING1-dependent ferroptosis [139]. CTSB can also act as a specific histone H3 protease and cleave H3 for ferroptosis [140]. In addition to inhibitors of lysosomal function (e.g., bafilomycin A1, ammonium chloride, pepstatin A, and CA-074Me), genetic blockade of cathepsin limits erastin-induced ferroptosis in cancer cells and MEFs [139, 140].
溶酶体膜电位增加是由各种细胞死亡刺激驱动的溶酶体依赖性细胞死亡的初始信号。最近，溶酶体组织蛋白酶的释放，特别是组织蛋白酶B (CTSB)，被认为是导致铁死亡的原因(图3b )。 CTSB 的上调和随后的溶酶体释放需要信号转导子和转录激活子 3 (STAT3) 的激活 [ 138 ]。 CTSB 通过至少两种潜在机制介导铁死亡。首先，CTSB 从溶酶体转移到细胞核，导致 DNA 损伤和随后的 STING1 依赖性铁死亡 [ 139 ]。 CTSB 还可以充当特定的组蛋白 H3 蛋白酶并裂解 H3 导致铁死亡 [ 140 ]。除了溶酶体功能抑制剂（例如巴弗洛霉素 A1、氯化铵、胃酶抑素 A 和 CA-074Me）之外，组织蛋白酶的基因阻断还可限制癌细胞和 MEF 中erastin 诱导的铁死亡[ 139 , 140 ]。

Other mechanisms of lysosomal-dependent ferroptosis involve the accumulation of lysosomal iron or nitric oxide (Fig. 3c) [141, 142]. This process is responsible for the dichloroacetate-induced inhibition of stemness in colorectal cancer cells [143], the loss of lysosomal protein prosaposin (PSAP)-mediated neuronal death [144], or nonthermal plasma-activated Ringer’s lactate-triggered ferroptosis in malignant mesothelioma cells [145]. As a defense mechanism, the activation of nuclear transcription factor EB (TFEB) can inhibit lysosomal-dependent ferroptosis by inducing antioxidant superoxide dismutase 1 (SOD1) gene expression [146]. CD44-mediated iron uptake in endocytic vesicles replenishes lysosomal iron, leading to increased sensitivity to ferroptosis [147]. Together, the crosstalk between the lysosome and the nucleus can establish a feedback mechanism for the modulation of ferroptosis. It is not clear whether lysosomal exocytosis results in membrane remodeling and repair during ferroptosis.
溶酶体依赖性铁死亡的其他机制涉及溶酶体铁或一氧化氮的积累（图3c ）[ 141 , 142 ]。该过程负责二氯乙酸诱导的结直肠癌细胞干性抑制[ 143 ]、溶酶体蛋白前塞塞蛋白（PSAP）介导的神经元死亡的丧失[ 144 ]或恶性间皮瘤中非热等离子体激活的林格氏乳酸触发的铁死亡。细胞[ 145 ]。作为一种防御机制，核转录因子EB（TFEB）的激活可以通过诱导抗氧化剂超氧化物歧化酶1（SOD1）基因表达来抑制溶酶体依赖性铁死亡[ 146 ]。内吞囊泡中 CD44 介导的铁摄取补充溶酶体铁，导致铁死亡的敏感性增加[ 147 ]。溶酶体和细胞核之间的串扰共同可以建立调节铁死亡的反馈机制。目前尚不清楚溶酶体胞吐作用是否会导致铁死亡过程中的膜重塑和修复。

Endoplasmic reticulum 内质网

Under normal conditions, the endoplasmic reticulum (ER) is the central organelle for the synthesis and processing of proteins as well as lipid secretion [148]. ER stress triggers an unfolded protein response to restore protein homeostasis, but can also trigger cell death when cells fail to restore homeostasis [149]. ER stress plays a dual role in ferroptosis (Fig. 4a). For example, erastin can induce a significant ER stress response by activating the eukaryotic translation initiation factor 2A (EIF2A)/activating transcription factor 4 (ATF4) pathway, which determines cell fate [20]. On one hand, ATF4-mediated HSPA5 expression prevents the degradation of GPX4, thereby increasing the resistance of pancreatic cancer cells or glioma cells to ferroptosis caused by gemcitabine or dihydroartemisinin [59, 150]. ATF4-mediated SLC7A11 upregulation is also implicated in ferroptosis resistance in human glioma cells [151]. On the other hand, the ATF4-mediated transcriptional expression of GSH-degrading enzyme ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) enhances artesunate- or cystine starvation-induced ferroptosis in breast cancer cells [152, 153]. Thus, the diversity of ATF4 target genes confer ATF4 multiple biological functions in ferroptosis. The ER stress response also contributes to artesunate- or erastin-induced ferroptosis via the activation of autophagic degradation [154]. In stark contrast, ER stress-associated Ca²⁺ influx triggers ESCRT-III accumulation in plasma membranes to prevent membrane damage during ferroptosis [76, 77]. Notably, ferrostatin-1 might exert its anti-ferroptotic effect through its accumulation in the ER, rather than in lysosomes and mitochondria [88]. Quantitative measurements by two-photon phosphorescent lifetime imaging revealed that the viscosity of the ER increases during erastin-induced ferroptosis [155]. These two studies further support the involvement of the ER in regulating ferroptosis.
正常情况下，内质网（ER）是蛋白质合成和加工以及脂质分泌的中心细胞器[ 148 ]。内质网应激会触发未折叠的蛋白质反应以恢复蛋白质稳态，但当细胞无法恢复稳态时也可能引发细胞死亡[ 149 ]。 ER应激在铁死亡中发挥双重作用（图4a ）。例如，erastin可以通过激活真核翻译起始因子2A（EIF2A）/激活转录因子4（ATF4）途径来诱导显着的内质网应激反应，从而决定细胞命运[ 20 ]。一方面，ATF4介导的HSPA5表达阻止GPX4的降解，从而增加胰腺癌细胞或神经胶质瘤细胞对吉西他滨或双氢青蒿素引起的铁死亡的抵抗力[ 59 , 150 ]。 ATF4 介导的 SLC7A11 上调也与人类神经胶质瘤细胞的铁死亡抵抗有关 [ 151 ]。另一方面，ATF4 介导的 GSH 降解酶 ChaC 谷胱甘肽特异性 γ-谷氨酰环转移酶 1 (CHAC1) 的转录表达可增强乳腺癌细胞中青蒿琥酯或胱氨酸饥饿诱导的铁死亡 [ 152 , 153 ]。因此，ATF4靶基因的多样性赋予ATF4在铁死亡中的多种生物学功能。内质网应激反应还通过激活自噬降解导致青蒿琥酯或erastin诱导的铁死亡[ 154 ]。形成鲜明对比的是，内质网应激相关的 Ca ²⁺流入触发 ESCRT-III 在质膜中积累，以防止铁死亡期间的膜损伤 [ 76 , 77 ]。 值得注意的是，ferrostatin-1 可能通过在内质网中积累来发挥其抗铁死亡作用，而不是在溶酶体和线粒体中[ 88 ]。双光子磷光寿命成像的定量测量表明，ER 的粘度在erastin 诱导的铁死亡过程中增加[ 155 ]。这两项研究进一步支持 ER 参与调节铁死亡。

Several ER proteins play a broad role in regulating ferroptosis sensitivity. For example, STING1, a transmembrane protein on the ER, is reported to translate the oxidative response of nuclear or mitochondrial structures into a ferroptotic response (Fig. 4b). STING1 depletion attenuates acute pancreatitis and KRAS-driven pancreatic tumor formation in mice that are prone to ferroptosis due to a high-iron diet or genetic GPX4 deletion in pancreatic acinar cells [156]. The oxidized nucleobase 8-hydroxyguanine (8-OHG) released by ferroptotic cells has been identified as a ligand for active STING1-dependent innate immunity in macrophages [156]. Mitochondrial damage caused by zalcitabine or erastin can trigger STING1-dependent ferroptosis in pancreatic cancer cells through convoluted pathways involving autophagy or mitochondrial fusion [21, 102]. As a negative feedback mechanism, unrestricted lipid peroxidation might reduce the transport of STING1 from the ER to the Golgi complex and the subsequent immune response by its carbonylation [157]. These findings underscore the multifunctional role of STING1 in mediating ferroptosis.
几种 ER 蛋白在调节铁死亡敏感性中发挥着广泛的作用。例如，据报道，ER上的跨膜蛋白STING1可将核或线粒体结构的氧化反应转化为铁死亡反应（图4b ）。 STING1 缺失可减轻小鼠的急性胰腺炎和 KRAS 驱动的胰腺肿瘤形成，这些小鼠由于高铁饮食或胰腺腺泡细胞中的遗传性 GPX4 缺失而容易发生铁死亡[ 156 ]。铁死亡细胞释放的氧化核碱基 8-羟基鸟嘌呤 (8-OHG) 已被确定为巨噬细胞中主动 STING1 依赖性先天免疫的配体 [ 156 ]。扎西他滨或erastin引起的线粒体损伤可以通过涉及自噬或线粒体融合的复杂途径触发胰腺癌细胞中STING1依赖性铁死亡[ 21 , 102 ]。作为一种负反馈机制，不受限制的脂质过氧化可能会减少 STING1 从 ER 到高尔基复合体的转运以及随后的羰基化免疫反应 [ 157 ]。这些发现强调了 STING1 在介导铁死亡中的多功能作用。

ER proteins can block ferroptosis, as exemplified by stearoyl-CoA desaturase (SCD). The biosynthesis of MUFA requires SCD, which competitively inhibits PUFA-mediated ferroptosis [48]. The expression of SCD is regulated by multiple factors, including transcription factors, kinases, hypoxia, and nutrition signals (Fig. 4c) [158]. For example, sterol regulatory element-binding transcription factor 1 (SREBF1, also known as SREBP1), a nuclear transcription factor regulating lipid metabolism, acts as a ferroptosis repressor by the induction of SCD expression [159, 160]. Ferroptosis inhibition by the SREBP1-SCD pathway can also result from the activation of pro-survival phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT-MTOR signaling in MDA-MB-453 and BT474 human breast cancer cells [159]. Lactate formed during anaerobic glycolysis inhibits the phosphorylation of AMPK, thereby activating the SREBP1-SCD pathway to inhibit ferroptosis in liver cancer cells [160]. The co-mutation of serine/threonine kinase 11 (STK11) and Kelch-like ECH-associated protein 1 (KEAP1) results in ferroptosis resistance in lung cancer cells partly through the upregulation of SCD [161]. Additionally, the nuclear protein F-box and WD repeat domain containing 7 (FBW7) can inhibit SCD expression in pancreatic cancer cells through blockade of nuclear receptor subfamily 4 group A member 1 (NR4A1) [162]. Thus, the combination of SCD inhibitors and ferroptosis inducers might be a potential strategy for anticancer treatment that warrants to be explored.
ER 蛋白可以阻止铁死亡，例如硬脂酰辅酶 A 去饱和酶 (SCD)。 MUFA的生物合成需要SCD，SCD竞争性地抑制PUFA介导的铁死亡[ 48 ]。 SCD的表达受到多种因素的调节，包括转录因子、激酶、缺氧和营养信号（图4c ）[ 158 ]。例如，甾醇调节元件结合转录因子 1（SREBF1，也称为 SREBP1）是一种调节脂质代谢的核转录因子，通过诱导 SCD 表达充当铁死亡阻遏物 [ 159 , 160 ]。 SREBP1-SCD 途径对铁死亡的抑制也可能是由于 MDA-MB-453 和 BT474 人乳腺癌细胞中促存活磷脂酰肌醇-4,5-二磷酸 3-激酶 (PI3K)-AKT-MTOR 信号传导的激活所致 [ 159] ]。无氧糖酵解过程中形成的乳酸抑制AMPK的磷酸化，从而激活SREBP1-SCD途径，抑制肝癌细胞的铁死亡[ 160 ]。丝氨酸/苏氨酸激酶 11 (STK11) 和 Kelch 样 ECH 相关蛋白 1 (KEAP1) 的共突变部分通过 SCD 的上调导致肺癌细胞铁死亡抵抗 [ 161 ]。此外，核蛋白 F-box 和 WD 重复结构域包含 7 (FBW7) 可以通过阻断核受体亚家族 4 A 组成员 1 (NR4A1) 抑制胰腺癌细胞中的 SCD 表达 [ 162 ]。因此，SCD抑制剂和铁死亡诱导剂的组合可能是值得探索的抗癌治疗的潜在策略。

In addition to iron, zinc ions have the ability to induce ferroptosis [163]. Solute carrier family 39 member 7 (SLC39A7, also known as ZIP7), a resident ER protein that mediates zinc transport from the ER to cytosol, is a promoter of ferroptosis (Fig. 4d) [163]. The inhibition of SLC39A7 triggers the expression of ER stress-associated genes, such as homocysteine-inducible ER protein with ubiquitin-like domain 1 (HERPUD1), which drives ferroptosis resistance [163]. These findings not only uncover an unexpected role for ER stress in mediating zinc-induced ferroptosis, but also challenge the current notion that ferroptosis is exclusively dominated by iron-dependent redox reactions. Since mitochondria can form contacts with the ER to regulate vital cellular homoeostatic functions [164], researchers should investigate these connections in ferroptosis.
除了铁之外，锌离子也具有诱导铁死亡的能力[ 163 ]。溶质载体家族 39 成员 7（SLC39A7，也称为 ZIP7）是一种驻留 ER 蛋白，介导锌从 ER 转运至细胞质，是铁死亡的启动子（图4d ）[ 163 ]。 SLC39A7 的抑制会触发 ER 应激相关基因的表达，例如具有泛素样结构域 1 的同型半胱氨酸诱导的 ER 蛋白 (HERPUD1)，该蛋白可驱动铁死亡抵抗 [ 163 ]。这些发现不仅揭示了内质网应激在介导锌诱导的铁死亡中的意想不到的作用，而且还挑战了目前铁死亡完全由铁依赖性氧化还原反应主导的观点。由于线粒体可以与内质网形成联系以调节重要的细胞稳态功能[ 164 ]，因此研究人员应该研究铁死亡中的这些联系。

Lipid droplets 脂滴

Lipid droplets (LDs) serve as storage organelles for neutral lipids, such as triacylglycerol and sterol esters. LDs are also in dynamic contact with other organelles (such as mitochondria, the ER, peroxisomes, and lysosomes) to facilitate the exchange of lipids, metabolites, and ions [165]. It is widely accepted that increasing the formation of LDs protects cells from PUFA-induced lipotoxicity and ER stress [166, 167]. The number of LDs increases in the early stages, but decreases in the final stages, of ferroptosis. The balance between the degradation and storage of LDs affects the sensitivity to ferroptosis. For example, RAB7A-mediated lipophagy increases intracellular PUFA production, thereby enhancing RSL3-induced ferroptosis in liver cancer cells. In contrast, tumor protein D52 (TPD52)-mediated lipid storage might limit ferroptosis by sequestering toxic oxidized lipids [8]. Exogenous PUFAs induces LD formation and accumulates in LDs, resulting in enhanced lipid ROS and ferroptosis in cervical (SiHa), colorectal (HCT-116), and hypopharyngeal (FaDu) cancer cells [168]. Moreover, Fas-associated factor family member 2 (FAF2), a molecule regulating LD formation and homeostasis, is downregulated in orlistat-induced ferroptosis in A549 and H1299 lung cancer cells, supporting the anti-ferroptotic role of LDs [169]. These observations highlight an urgent need to uncover the mechanisms of the LD dynamics in ferroptosis. In addition, lipolysis (the hydrolysis of triacylglycerol) occurs on the surface of LDs, releasing fatty acids for bioenergetic or anabolic reactions. Several enzymes, such as patatin-like phospholipase domain containing 2 (PNPLA2, also known as ATGL) and lipase E, hormone-sensitive type (LIPE, also known as HSL), play crucial roles in lipolysis [170], but their precise roles in ferroptosis remain to be uncovered.
脂滴（LD）充当中性脂质（例如三酰甘油和甾醇酯）的储存细胞器。 LD 还与其他细胞器（例如线粒体、ER、过氧化物酶体和溶酶体）动态接触，以促进脂质、代谢物和离子的交换[ 165 ]。人们普遍认为，增加 LD 的形成可以保护细胞免受 PUFA 诱导的脂毒性和 ER 应激的影响 [ 166 , 167 ]。 LD 的数量在铁死亡的早期阶段增加，但在最终阶段减少。 LD 的降解和储存之间的平衡会影响对铁死亡的敏感性。例如，RAB7A 介导的脂肪吞噬增加了细胞内 PUFA 的产生，从而增强了 RSL3 诱导的肝癌细胞中的铁死亡。相反，肿瘤蛋白 D52 (TPD52) 介导的脂质储存可能通过隔离有毒的氧化脂质来限制铁死亡 [ 8 ]。外源性 PUFA 诱导 LD 形成并在 LD 中积累，导致宫颈 (SiHa)、结直肠 (HCT-116) 和下咽 (FaDu) 癌细胞中脂质 ROS 增强和铁死亡[ 168 ]。此外，Fas相关因子家族成员2（FAF2）是一种调节LD形成和稳态的分子，在A549和H1299肺癌细胞中奥利司他诱导的铁死亡中下调，支持LD的抗铁死亡作用[ 169 ]。这些观察结果强调迫切需要揭示铁死亡中 LD 动力学的机制。此外，脂解作用（三酰甘油的水解）发生在 LD 表面，释放脂肪酸用于生物能或合成代谢反应。 几种酶，例如patatin样磷脂酶结构域2（PNPLA2，也称为ATGL）和脂肪酶E，激素敏感型（LIPE，也称为HSL），在脂肪分解中发挥着至关重要的作用[ 170 ]，但它们的确切作用铁死亡仍有待发现。

Peroxisomes 过氧化物酶体

Peroxisomes are organelles that generate ROS and reactive nitrogen species (RNS) through pro-oxidant enzymes, such as xanthine dehydrogenase (XDH) and nitric oxide synthase 2 (NOS2) [171]. Conversely, peroxisomes also contain antioxidant enzymes, such as catalase (CAT), SOD1, peroxiredoxin 5 (PRDX5), and glutathione S-transferase kappa 1 (GSTK1) [172]. Nonetheless, a recent study showed that peroxisome-mediated lipid synthesis rather than ROS or RNS generation promotes ferroptosis [54]. In particular, ether lipids are synthesized through a well-characterized process that begins in peroxisomes and finishes in the ER [54]. Within peroxisomes, the enzymes fatty acyl-CoA reductase 1 (FAR1) and alkylglycerone phosphate synthase (AGPS) catalyze the biosynthesis of the ether lipid precursor 1-O-alkyl-glycerol-3-phosphate (AGP). The is then delivered to the ER where it is acylated and dehydrogenated to form plasmalogens. The knockdown of peroxisome resident enzymes FAR1 and AGPS, or ER resident enzyme 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), diminishes the sensitivity of the cells to ferroptosis induced by GPX4 inhibition [54]. Consistently, the knockdown of peroxisomal biogenesis factors (PEXs), including PEX3, PEX10, PEX16, and PEX19, limits the production of polyunsaturated ether phospholipids (PUFA-ePLs), especially plasmalogens [54, 173]. Moreover, plasmanylethanolamine desaturase 1 (PEDS1, also known as TMEM189), which introduces the characteristic vinyl ether double bond into plasmalogens [174], limits ferroptosis through downregulating FAR1 protein levels [173]. These findings support the key role of peroxisome-driven PUFA-ePLs in modulating susceptibility to ferroptosis [175]. However, neurons from plasmalogen-deficient (PEX7 knockout) mice are more susceptible to ROS-mediated damage [176], indicating that ether phospholipids might act as endogenous antioxidants as well. In addition to lipid synthesis and redox balance, peroxisomes are also involved in the biosynthesis and signaling of steroid and peptide hormones [177], which in turn might indirectly impinge on the regulation of ferroptosis.
过氧化物酶体是通过促氧化酶（例如黄嘌呤脱氢酶（XDH）和一氧化氮合酶 2（NOS2））产生 ROS 和活性氮（RNS）的细胞器[ 171 ]。相反，过氧化物酶体还含有抗氧化酶，例如过氧化氢酶（CAT）、SOD1、过氧化还原蛋白5（PRDX5）和谷胱甘肽S-转移酶kappa 1（GSTK1）[ 172 ]。尽管如此，最近的一项研究表明，过氧化物酶体介导的脂质合成而不是ROS或RNS的生成促进了铁死亡[ 54 ]。特别是，醚脂是通过一个充分表征的过程合成的，该过程从过氧化物酶体开始并在内质网中结束[ 54 ]。在过氧化物酶体中，脂肪酰辅酶 A 还原酶 1 (FAR1) 和烷基甘油磷酸合酶 (AGPS) 催化醚脂质前体 1-O-烷基-甘油-3-磷酸 (AGP) 的生物合成。然后被输送到内质网，在那里被酰化和脱氢形成缩醛磷脂。过氧化物酶体驻留酶 FAR1 和 AGPS 或 ER 驻留酶 1-酰基甘油-3-磷酸 O-酰基转移酶 3 (AGPAT3) 的敲低可降低细胞对 GPX4 抑制诱导的铁死亡的敏感性 [ 54 ]。一致地，过氧化物酶体生物发生因子 (PEX)，包括 PEX3、PEX10、PEX16 和 PEX19 的敲低，限制了多不饱和醚磷脂 (PUFA-ePL)，尤其是缩醛磷脂的产生 [ 54 , 173 ]。此外，血浆酰乙醇胺去饱和酶1（PEDS1，也称为TMEM189）将特征性乙烯基醚双键引入缩醛磷脂[ 174 ]，通过下调FAR1蛋白水平来限制铁死亡[ 173 ]。 这些发现支持过氧化物酶体驱动的 PUFA-ePL 在调节铁死亡易感性中的关键作用[ 175 ]。然而，缩醛磷脂缺陷（PEX7 敲除）小鼠的神经元更容易受到 ROS 介导的损伤[ 176 ]，这表明醚磷脂也可能充当内源性抗氧化剂。除了脂质合成和氧化还原平衡之外，过氧化物酶体还参与类固醇和肽激素的生物合成和信号传导[ 177 ]，这反过来可能间接影响铁死亡的调节。

Golgi apparatus 高尔基体

The Golgi apparatus, a membranous organelle, has important functions in processing and sorting lipids and proteins for secretion or cellular use. Pharmacological Golgi stress inducers (e.g., AMF-26/M-COPA, brefeldin A, and golgicide A) trigger ferroptosis in HeLa cells, and this can be avoided by overexpression of SLC7A11 or GPX4, as well as the depletion of ACSL4 [178], indicating that Golgi-dependent ferroptosis requires classical ferroptotic regulators. The induction of ferroptosis by brefeldin A is also influenced by the availability of extracellular cystine [178]. The transsulfuration pathway (a source of cysteine for GSH in cells) can protect cells against brefeldin A-induced ferroptosis [178]. Although the exact mechanism of Golgi stress-induced ferroptosis is still poorly understood, it is suspected that Golgi dispersal might induce the loss of antioxidant molecules (e.g., CoQ10) [179]. Regardless, the sorting and transportation of cellular cargos in the entire cell by the Golgi apparatus might be impaired during ferroptosis, hence exemplifying yet another pathway in which disrupted protein homeostasis contributes to cell death.
高尔基体是一种膜细胞器，在处理和分类脂质和蛋白质以供分泌或细胞使用方面具有重要功能。药理学高尔基体应激诱导剂（例如，AMF-26/M-COPA、布雷菲德菌素 A 和高尔基剂 A）会引发 HeLa 细胞中的铁死亡，这可以通过 SLC7A11 或 GPX4 的过度表达以及 ACSL4 的耗尽来避免[ 178 ] ，表明高尔基体依赖性铁死亡需要经典的铁死亡调节剂。布雷菲德菌素 A 诱导的铁死亡也受到细胞外胱氨酸可用性的影响 [ 178 ]。转硫途径（细胞中 GSH 的半胱氨酸来源）可以保护细胞免受布雷菲德菌素 A 诱导的铁死亡 [ 178 ]。尽管高尔基体应激诱导铁死亡的确切机制仍知之甚少，但人们怀疑高尔基体分散可能会导致抗氧化分子（例如辅酶Q10）的损失[ 179 ]。无论如何，高尔基体在整个细胞中对细胞货物的分类和运输可能在铁死亡过程中受到损害，因此例证了蛋白质稳态被破坏导致细胞死亡的另一种途径。

Nucleus 核

In a previous review, we discussed the contribution of various transcription factors to the regulation of ferroptosis [180]. Here, we will focus on the discussion of non-transcriptional aspects of the nuclear implication in ferroptosis. Although early studies did not detect any obvious morphological changes in the nucleus, oxidative damage of nuclear DNA is a biochemical correlate of ferroptosis, which is associated with nuclear DAMP (e.g., HMGB1) release [10]. Several DNA damage response pathways, such as TP53, ataxia telangiectasia mutated (ATM), and FA complementation group D2 (FANCD2), play a context-dependent role in inhibiting or promoting ferroptosis. For example, TP53 activation can promote ferroptosis by the downregulation of SLC7A11 in breast cancer cells [62], whereas TP53 loss can trigger ferroptosis by activating the dipeptidyl peptidase 4 (DPP4)-dependent NOX pathway in colon cancer cells [27]. Radiotherapy-activated ATM transcriptionally represses SLC7A11 expression to promote ferroptosis in HT1080 cells [181]. FANCD2-mediated DNA repair inhibits erastin-induced ferroptosis in bone marrow cells [182]. The iron-binding protein pirin (PIR) is a nuclear redox-sensor, which limits autophagy-dependent ferroptosis by retaining HMGB1 in the nucleus [183]. In contrast, the translocation of lysosomal CTSB [139, 140] or mitochondrial AIFM1 [99, 100] to the nucleus can cause local damage and induce ferroptotic cell death. Thus, the translocation of different proteins between nuclear and extranuclear compartments profoundly affects the susceptibility of cells to ferroptosis. Future proteomic studies should provide a systematic and refined analysis of such ferroptosis-relevant translocation events.
在之前的综述中，我们讨论了各种转录因子对铁死亡调节的贡献[ 180 ]。在这里，我们将重点讨论铁死亡中核影响的非转录方面。尽管早期研究没有检测到细胞核有任何明显的形态变化，但核DNA的氧化损伤是铁死亡的生化相关因素，铁死亡与核DAMP（例如HMGB1）的释放有关[ 10 ]。多种 DNA 损伤反应途径，例如 TP53、共济失调毛细血管扩张突变 (ATM) 和 FA 补充组 D2 (FANCD2)，在抑制或促进铁死亡方面发挥着背景依赖性作用。例如，TP53的激活可以通过下调乳腺癌细胞中的SLC7A11来促进铁死亡[ 62 ]，而TP53的缺失可以通过激活结肠癌细胞中的二肽基肽酶4（DPP4）依赖性NOX途径来引发铁死亡[ 27 ]。放射治疗激活的 ATM 转录抑制 SLC7A11 表达，促进 HT1080 细胞铁死亡[ 181 ]。 FANCD2 介导的 DNA 修复抑制erastin 诱导的骨髓细胞铁死亡[ 182 ]。铁结合蛋白 Pirin (PIR) 是一种核氧化还原传感器，通过将 HMGB1 保留在细胞核中来限制自噬依赖性铁死亡 [ 183 ]​​。相反，溶酶体 CTSB [ 139 , 140 ] 或线粒体 AIFM1 [ 99 , 100 ] 易位至细胞核可引起局部损伤并诱导铁死亡。因此，不同蛋白质在核和核外区室之间的易位深刻地影响细胞对铁死亡的易感性。 未来的蛋白质组学研究应该对这种与铁死亡相关的易位事件提供系统和精细的分析。