Ferritinophagy: research advance and clinical significance in cancers
铁蛋白自噬：癌症的研究进展及临床意义

Ferritinophagy and autophagy
铁蛋白自噬和自噬

Ferritinophagy is a process by which cells degrade and recycle ferritin. And this process is mediated by autophagy, a cellular process in which damaged or unwanted cellular components are engulfed by double-membrane structures called autophagosomes and targeted for degradation by lysosomes. Ferritinophagy is a selective form of autophagy, and excess intracellular ferritin can induce iron-mediated apoptosis through autophagy by the selective autophagy receptor NCOA4 [9] which is the special molecule distinguished from other forms of autophagy (Fig. 1a). Furthermore, the process of ferritinophagy-induced cell death leads to the release of the proteoglycan decorin. This release serves as a signaling mechanism to activate both innate and adaptive immune responses, as well as the release of inflammatory factors including tumor necrosis factor and interleukin-6 (IL-6) [10, 11]. Inducing immunogenic necrosis of cancer cells can also activate anti-tumor immune response in vivo. ATP and HMGB1 are damage related substances of immunogenic cell death, which have been shown to be released during Ferroptosis and act as an immunogenic signal associated with the immunogenicity of iron-dead cancer cells [12]. Consequently, ferritinophagy exhibits distinct immune response characteristics. Moreover, ferritinophagy also has the characteristics of general autophagy, such as the altered expression content of autophagy-related genes autophagy related 5 (ATG5) and autophagy related 7 (ATG7) [13], increased LC3II/LC3I ratio [14] and genomic instability and mutations (Fig. 1b). It has been demonstrated that ferritinophagy in diffuse B-cell lymphoma cells triggered by eprenetapopt (APR-246) is characterized by tumor protein p53 (TP53) mutations [15]. Macroautophagy, endosomal microautophagy and ferritinophagy all also require the participation of Tax1 binding protein 1 (TAX1BP1) [16].
铁蛋白自噬是细胞降解和回收铁蛋白的过程。这个过程是由自噬介导的，自噬是一种细胞过程，其中受损或不需要的细胞成分被称为自噬体的双膜结构吞噬，并被溶酶体靶向降解。铁蛋白自噬是自噬的一种选择性形式，过量的细胞内铁蛋白可以通过选择性自噬受体 NCOA4 的自噬诱导铁介导的细胞凋亡。 9 ]是区别于其他形式自噬的特殊分子（图1）。 1a ）。此外，铁蛋白吞噬诱导的细胞死亡过程导致蛋白聚糖核心蛋白聚糖的释放。这种释放作为一种信号机制来激活先天性和适应性免疫反应，以及炎症因子的释放，包括肿瘤坏死因子和白细胞介素 6 (IL-6)。 10 , 11 ]。诱导癌细胞的免疫原性坏死还可以激活体内抗肿瘤免疫反应。 ATP 和 HMGB1 是免疫原性细胞死亡的损伤相关物质，已被证明在铁死亡过程中释放，并充当与铁死亡癌细胞的免疫原性相关的免疫原性信号。 12 ]。因此，铁蛋白自噬表现出独特的免疫反应特征。此外，铁蛋白自噬还具有一般自噬的特征，如自噬相关基因自噬相关5（ATG5）和自噬相关7（ATG7）表达内容的改变。 13 ]，增加 LC3II/LC3I 比率 [ 14 ]以及基因组不稳定性和突变（图1）。 1b ）。 已证明 eprenetapopt (APR-246) 引发的弥漫性 B 细胞淋巴瘤细胞中的铁蛋白自噬以肿瘤蛋白 p53 (TP53) 突变为特征。 15 ]。巨自噬、内体微自噬和铁蛋白自噬也都需要 Tax1 结合蛋白 1 (TAX1BP1) 的参与 [ 16 ]。

Ferritinophagy and ferroptosis
铁蛋白自噬和铁死亡

Ferritinophagy is the apoptotic pathway of ferroptosis, which has common characteristics with ferroptosis but different from ferroptosis (Table 1).
铁蛋白自噬是铁死亡的凋亡途径，与铁死亡有共同特征，但又不同于铁死亡（表 1 ）。

Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of LPOs [17], which is generated by the iron-dependent oxidation of polyunsaturated fatty acids [18]. The accumulation of LPOs in the cell membrane leads to membrane damage and ultimately, cell death. Ferroptosis is regulated by a variety of factors, including iron, glutathione peroxidase 4 (GPX4), and other antioxidant enzymes [19, 20]. Additionally, ferroptosis disrupts the equilibrium between redox reactions and promotes oxidative damage to cellular organelles. This oxidative damage manifests in morphological changes such as smaller mitochondria, reduced or absent mitochondrial cristae, and concentrated rupture of the outer mitochondrial membrane [21–25]. In addition to the imbalance of antioxidant system caused by excessive accumulation of LPOs, the disorder of amino acid metabolism and nucleotide metabolism is also related to ferroptosis [26]. In contrast to the autophagy receptor NCOA4, which is unique to ferritinophagy, a new ferroptosis receptor, Hippocalcin like 1, is also recently identified [27]. Compared to the ferroptosis specific molecular markers GPX4, prostaglandin-endoperoxidesynthase2, solute carrier family 7 member 11 (SLC7A11), acyl-CoA synthetase long-chain family member 4, regulator of G-protein signaling 4, single stranded DNA binding protein 1 (SSBP1) [28], it has been observed that ferritinophagy controls disturbed protein mechanisms encoding and regulating iron transcripts, including differences in miRNA, methylation and acetylation [29]. Histone ubiquitination, methylation, miRNA, and the immune microenvironment also modulate ferroptosis in cancer cells [30–33].
铁死亡是一种铁依赖形式的程序性细胞死亡，其特征是 LPO 的积累。 17 ]，它是由多不饱和脂肪酸的铁依赖性氧化产生的[ 18 ]。 LPO 在细胞膜中的积累会导致膜损伤，并最终导致细胞死亡。铁死亡受多种因素调节，包括铁、谷胱甘肽过氧化物酶 4 (GPX4) 和其他抗氧化酶。 19 , 20 ]。此外，铁死亡会破坏氧化还原反应之间的平衡，并促进细胞器的氧化损伤。这种氧化损伤表现为形态变化，例如线粒体变小、线粒体嵴减少或缺失以及线粒体外膜集中破裂。 21 – 25 ]。除了LPO过度积累导致抗氧化系统失衡外，氨基酸代谢和核苷酸代谢紊乱也与铁死亡有关。 26 ]。与铁蛋白自噬所特有的自噬受体 NCOA4 相比，最近还发现了一种新的铁死亡受体 Hippocalcin like 1。 27 ]。与铁死亡特异性分子标记 GPX4、前列腺素内过氧化物合酶 2、溶质载体家族 7 成员 11 (SLC7A11)、酰基辅酶 A 合成酶长链家族成员 4、G 蛋白信号调节因子 4、单链 DNA 结合蛋白 1 (SSBP1) 相比）[ 28 ]，据观察，铁蛋白自噬控制编码和调节铁转录本的蛋白质机制受到干扰，包括 miRNA、甲基化和乙酰化的差异[ 29 ]。 组蛋白泛素化、甲基化、miRNA 和免疫微环境也调节癌细胞的铁死亡。 30 – 33 ]。

Although ferroptosis and ferritinophagy are distinct processes, they are both involved in the regulation of iron metabolism in cells. Ferroptosis can lead to the release of iron from cells, while ferritinophagy can increase the availability of iron for cellular use. The precise relationship between these two processes and their role in iron metabolism is an active area of research [34].
尽管铁死亡和铁蛋白自噬是不同的过程，但它们都参与细胞内铁代谢的调节。铁死亡可导致细胞释放铁，而铁蛋白自噬可增加细胞使用铁的可用性。这两个过程之间的精确关系及其在铁代谢中的作用是一个活跃的研究领域。 34 ]。

Ferritinophagy regulatory mechanism
铁蛋白自噬调控机制

Ferritinophagy is regulated by several mechanisms that control both synthesis and degradation of ferritin. One of the key regulatory mechanisms is the control of intracellular iron levels, which can trigger or inhibit the process of ferritinophagy in response to the changes in cellular iron homeostasis. First, ferritin binds to NCOA4 via the FTH1 subunit to form a complex. Next, the double walled proto-autophagosome membrane contains the ferritin-NCOA4 complex to form a completely closed structure. Finally, the autophagosomes transfer to the lysosomes and fuse with each other, and the ferritin degrades and releases iron in the lysosomes [35]. Among them, intracellular proteins involved in the regulation of iron homeostasis also affect the sensitivity of cells to ferritinophagy.
铁蛋白吞噬受到多种控制铁蛋白合成和降解的机制的调节。关键的调节机制之一是细胞内铁水平的控制，它可以响应细胞铁稳态的变化而触发或抑制铁蛋白自噬过程。首先，铁蛋白通过 FTH1 亚基与 NCOA4 结合形成复合物。接下来，双壁原自噬体膜含有铁蛋白-NCOA4复合物，形成完全封闭的结构。最后，自噬体转移到溶酶体并相互融合，铁蛋白在溶酶体中降解并释放铁。 35 ]。其中，参与铁稳态调节的细胞内蛋白也影响细胞对铁蛋白自噬的敏感性。

Ferritinophagy is dependent on the selective ferritin degradation of iron as it is sensitive to iron ions and the iron transport proteins expression. The intracellular iron atom has a complete iron regulatory network. Once the iron uptake increase, a decrease in iron export or stores due to autophagic degradation of ferritin can result in the development and progression of ferroptosis promoted [36, 37].
铁蛋白吞噬依赖于铁的选择性铁蛋白降解，因为它对铁离子和铁转运蛋白表达敏感。细胞内铁原子具有完整的铁调节网络。一旦铁摄入增加，铁蛋白自噬降解导致铁输出或储存减少，可导致铁死亡的发生和进展。 36 , 37 ]。

Regulation of ferritinophagy through NCOA4
通过 NCOA4 调节铁蛋白吞噬

Ferritin is a cellular iron storage complex that can undergo lysosomal degradation via the selective autophagic adapter NCOA4, releasing iron for cellular use. Current studies have shown that alterations in many molecules can regulate the occurrence of iron autophagy by modulating the expression of NCOA4. For example, autophagy-associated genes (ATG) can activate NCOA4, and overexpression of NCOA4 promotes intracellular iron ion transportation and cellular ferritinophagy, thereby inducing ferroptosis [38, 39]. While knockdown of NCOA4 or ATG significantly reverses the reduction of transferrin, attenuates iron overload and lipid peroxidation, and alleviates cellular ferroptosis [40]. DNA double-strand break-related genes ataxia telangiectasia mutated (ATM) is indispensable in ferroptosis, and ATM can promote NCOA4-ferritin interactions to maintain ferritinophagy by phosphorylating NCOA4 [41]. Not only can changes at the molecular level affect NCOA4 expression, but signaling pathways can also regulate NCOA4 expression. In cells, NCOA4 binds to FTH1 and then connects to LC3II in the lysosome, releasing ferrous iron and enhancing the Fenton reaction to promote ferritinophagy, thus inducing the onset of ferroptosis [10, 42, 43]. The interaction between NCOA4 and FTH1 can be blocked by yes-associated protein 1, a key regulator of the Hippo signaling pathway, who can down-regulates GPX4, FTH1 and SLC7A11, and up-regulates siderofexin (SFXN1) and NCOA4 to reduce ROS production to inhibit hepatocyte ferroptosis [44]. NCOA4 is also regulated by the IL-6/STAT3 signaling pathway, which protects cardiomyocytes from ferritinophagy mediated ferroptosis by inhibiting STAT3 [45]. SUN et al. demonstrated that NCOA4 is dependent on the regulation of the JNK-JUN signaling pathway where JUN can bind to the promoter of NCOA4 to inhibit the interaction between NCOA4 and ferritin, thereby increasing ferritin autophagic degradation and promoting ferroptosis in chondrocytes [46]. In addition, heat damage or ionizing radiation can also cause cellular damage through NCOA4-mediated ferritinophagy [47–50]. All of above suggest that NCOA4 expression is associated with ferritinophagy in cancer cells [51, 52] (Fig. 2).
铁蛋白是一种细胞铁储存复合物，可以通过选择性自噬接头 NCOA4 进行溶酶体降解，释放铁供细胞使用。目前的研究表明，许多分子的改变可以通过调节NCOA4的表达来调节铁自噬的发生。例如，自噬相关基因（ATG）可以激活NCOA4，NCOA4的过度表达促进细胞内铁离子运输和细胞铁蛋白自噬，从而诱导铁死亡。 38 , 39 ]。虽然 NCOA4 或 ATG 的敲低可显着逆转转铁蛋白的减少，减轻铁过载和脂质过氧化，并减轻细胞铁死亡。 40 ]。 DNA双链断裂相关基因共济失调毛细血管扩张突变（ATM）在铁死亡中必不可少，ATM可以通过磷酸化NCOA4促进NCOA4-铁蛋白相互作用以维持铁蛋白自噬。 41 ]。不仅分子水平的变化可以影响NCOA4的表达，信号通路也可以调节NCOA4的表达。在细胞中，NCOA4与FTH1结合，然后在溶酶体中与LC3II连接，释放亚铁并增强Fenton反应，促进铁蛋白自噬，从而诱导铁死亡的发生。 10 , 42 , 43 ]。 NCOA4 和 FTH1 之间的相互作用可以被 yes 相关蛋白 1 阻断，yes 相关蛋白 1 是 Hippo 信号通路的关键调节因子，它可以下调 GPX4、FTH1 和 SLC7A11，上调 siderofexin (SFXN1) 和 NCOA4，从而减少 ROS 产生抑制肝细胞铁死亡[ 44 ]。 NCOA4 还受 IL-6/STAT3 信号通路的调节，通过抑制 STAT3 来保护心肌细胞免受铁蛋白自噬介导的铁死亡。 45 ]。孙等人。 证明NCOA4依赖于JNK-JUN信号通路的调节，其中JUN可以与NCOA4的启动子结合，抑制NCOA4与铁蛋白之间的相互作用，从而增加铁蛋白自噬降解并促进软骨细胞铁死亡。 46 ]。此外，热损伤或电离辐射也会通过 NCOA4 介导的铁蛋白自噬造成细胞损伤。 47 – 50 ]。所有这些都表明 NCOA4 表达与癌细胞中的铁蛋白自噬相关。 51 , 52 ] （如图。 2 ）。

Ferritinophagy promotes cell death and inhibit Epithelial-Mesenchymal Transition (EMT) by affecting the lipid peroxidation pathway
铁蛋白自噬通过影响脂质过氧化途径促进细胞死亡并抑制上皮间质转化（EMT）

Unrestricted cellular proliferation is a notable pathological characteristic observed in cancer. The process of ferritinophagy initiates lipid peroxidation, resulting in membrane impairment and cellular demise by degrading ferritin, all of which are closely linked to the progression of cancer. Genes or pathways that regulate the lipid peroxidation system have an impact on the growth and development of cancer cells [74, 75]. Genes or pathways that regulate the lipid peroxidation system have an impact on the growth and development of cancer cells. For instance, iron chelator 2-pyridylhydrazone dithiocarbamate s-acetate acid (PdtaA) has been found to enhance the production of reactive oxygen species (ROS) and induce cell cycle arrest in HepG2 cells through ferritinophagy [76]. Additionally, PdtaA down-regulates GPX4 and xCT, leading to ferroptosis. Another research team has demonstrated the chelator’s ability to inhibit epithelial-mesenchymal transition (EMT) in gastric cancer cells through ferritinophagy mediated the ROS/p53 pathway [77] (Fig. 4a). The resulting increased lipid peroxide production can promote autophagy-mediated ferroptosis in cancer cells.
不受限制的细胞增殖是癌症中观察到的显着病理特征。铁蛋白吞噬过程会引发脂质过氧化，通过铁蛋白降解导致膜损伤和细胞死亡，所有这些都与癌症的进展密切相关。调节脂质过氧化系统的基因或途径对癌细胞的生长和发育有影响。 74 , 75 ]。调节脂质过氧化系统的基因或途径对癌细胞的生长和发育有影响。例如，铁螯合剂 2-吡啶腙二硫代氨基甲酸酯 s-乙酸 (PdtaA) 已被发现可增强活性氧 (ROS) 的产生，并通过铁蛋白自噬诱导 HepG2 细胞的细胞周期停滞。 76 ]。此外，PdtaA 下调 GPX4 和 xCT，导致铁死亡。另一个研究小组证明了螯合剂能够通过铁蛋白自噬介导的 ROS/p53 途径抑制胃癌细胞的上皮间质转化 (EMT)。 77 ] （如图。 4a ）。由此产生的脂质过氧化物产量增加可以促进癌细胞中自噬介导的铁死亡。

Ferritinophagy inhibits cancer cell growth through the mediation of NCOA4
铁蛋白自噬通过 NCOA4 的介导抑制癌细胞生长

Cellular autophagic processes inhibit cancer cell activity mediated by ferritin. The main mode of iron released from ferritin is selective autophagy mediated by NCOA4, therefore, NCOA4-mediated ferritinophagy has a key role in cancer progression. For instance, the inhibition of coatomer protein complex subunit zeta 1 (COPZ1) leads to a decrease in glioblastoma (GBM) cell proliferation through the upregulation of NCOA4 and the facilitation of ferritin degradation [78]. TRIM7’s K48-linked chain directly binds to NCOA4 and ubiquitinates it, thereby impeding the growth of human GBM cells mediated by NCOA4 and promoting ferritinophagy [79] (Fig. 4b).
细胞自噬过程抑制铁蛋白介导的癌细胞活性。铁蛋白释放铁的主要方式是NCOA4介导的选择性自噬，因此NCOA4介导的铁蛋白自噬在癌症进展中具有关键作用。例如，抑制外壳蛋白复合物亚基 zeta 1 (COPZ1) 通过上调 NCOA4 和促进铁蛋白降解，导致胶质母细胞瘤 (GBM) 细胞增殖减少。 78 ]。 TRIM7的K48连接链直接与NCOA4结合并将其泛素化，从而阻碍NCOA4介导的人GBM细胞的生长并促进铁蛋白自噬。 79 ] （如图。 4b ）。

Ferritinophagy and immune response coordinate anti-cancer
铁蛋白自噬和免疫反应协调抗癌

The body is susceptible to interference by foreign pathogens when its immune function is reduced, and cancers are prone to occur at this time. Cancer cells that die from ferritinophagy release certain molecules to stimulate the immune system to fight against cancers, and enhanced ferritinophagy and immune activation can synergistically reinforce each other in inducing cancer cell death. NCOA4 not only facilitates cellular ferritinophagy but also plays a role in cancer cell-mediated immune responses. For instance, the diminished expression of NCOA4 in renal clear cell carcinoma has been found to govern unfavorable cancer prognosis and impaired infiltration of immune cells. In the present study, it was observed that CD8+ T cells activated through immunotherapy can effectively induce cancer cell death by augmenting lipid peroxidation in cancer cells [51] (Fig. 4c). Furthermore, NCOA4 can act as a target for macrophages to regulate iron overload and as a signal for inflammatory molecules [80].
人体免疫功能降低时，容易受到外来病原体的干扰，此时就容易发生癌症。死于铁蛋白自噬的癌细胞会释放某些分子来刺激免疫系统对抗癌症，增强的铁蛋白自噬和免疫激活可以协同增强彼此诱导癌细胞死亡的作用。 NCOA4 不仅促进细胞铁蛋白自噬，还在癌细胞介导的免疫反应中发挥作用。例如，已发现肾透明细胞癌中 NCOA4 表达的减少会导致癌症预后不良和免疫细胞浸润受损。在本研究中，观察到通过免疫疗法激活的CD8+ T细胞可以通过增强癌细胞中的脂质过氧化来有效诱导癌细胞死亡。 51 ] （如图。 4c ）。此外，NCOA4 可以作为巨噬细胞的靶标来调节铁过载，并作为炎症分子的信号。 80 ]。

Ferritinophagy in non-cancer
非癌症中的铁蛋白自噬

Currently, ferritinophagy primarily exhibits an anti-cancer effect in cancers, although there is evidence suggesting that the regulation of ferritinophagy-related pathways does not impact cell function. For example, the silencing of NCOA4 in colon cancer cells did not yield any noteworthy disparity in the expression of ferritin and TFR1, thereby suggesting that the growth of colon cancer cells does not necessitate the participation of ferritinophagy [81]. During the investigation into the process of lipid peroxide formation in ferritinophagy, a research team conducted experiments that revealed the ability of the ferroptosis inducer erastin to promote ferritinophagy in HeLa cells expressing NCOA4. Conversely, another ferroptosis inducer, RAS-selective lethal 3, was found to delay the death of HeLa cells overexpressing NCOA4 [82]. This demonstrates that whether ferritinophagy can regulate the onset of ferroptosis depended on the inducing compounds and the downstream pathways activated by cell death.
目前，铁蛋白自噬主要在癌症中表现出抗癌作用，尽管有证据表明铁蛋白自噬相关途径的调节不会影响细胞功能。例如，结肠癌细胞中 NCOA4 的沉默并未导致铁蛋白和 TFR1 的表达出现任何显着差异，从而表明结肠癌细胞的生长不需要铁蛋白自噬的参与。 81 ]。在研究铁蛋白自噬中脂质过氧化物形成过程的过程中，一个研究小组进行的实验揭示了铁死亡诱导剂erastin在表达NCOA4的HeLa细胞中促进铁蛋白自噬的能力。相反，另一种铁死亡诱导剂 RAS 选择性致死 3 被发现可以延迟过度表达 NCOA4 的 HeLa 细胞的死亡。 82 ]。这表明铁蛋白自噬是否可以调节铁死亡的发生取决于诱导化合物和细胞死亡激活的下游途径。

Chemotherapy exert anti-cancer effect by targeting ferritinophagy
化疗通过靶向铁蛋白吞噬发挥抗癌作用

Autophagy is an adaptive response to metabolic and therapeutic stress in a manner that can be applied to clinical therapeutic targets and prognostic monitoring. Regulation of any process in the ferritinophagy pathway can lead to cellular alterations. In the first place, NCOA4 plays a role in cancer therapy. Studies have shown that lipopolysaccharide (LPS) can regulate ferritin conversion by inhibiting NCOA4 as a therapeutic target for cancer [83]. Powdered tetrandrine citrate (TetC), a novel highly water-soluble powdered cycloheximide salt, has strong anticancer activity not only in chronic myeloid leukemia, but also in breast cancer cells by inhibiting GPX4 expression and activation of NCOA4 to promote ferritinophagy in cancer cells inducing ferrogenic cell death [80]. In addition, other pathways have been validated in ferritinophagy-mediated cancer therapy. For example, the process of iron transportation into mitochondria by lysosomes during ferritinophagy can serve as a potential target for enhancing pancreatic cancer survival rates and overcoming treatment resistance [84]. The reactive oxygen species (ROS) generated through ferritinophagy can activate the p53 and PHD2/HIF-1α signaling pathways, while also inhibiting the iron chelator 2,2’-di-pyridylketone hydrazone dithiocarbamate s-butyric acid (DpdtbA), thereby inducing EMT in gastric cancer cells [85]. The administration of the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells reliant on ferritinophagy triggers the ferroptosis process. Consequently, cancer cells treated with JQ1 exhibit an increased LC3II/LC3I ratio, reduced FTH1 expression, and decreased expression of autophagy-related genes ATG5 and ATG7 [86]. Above demonstrating that more and more ferritinophagy-related molecules are becoming targets in cancer therapy.
自噬是对代谢和治疗应激的适应性反应，可应用于临床治疗目标和预后监测。调节铁蛋白自噬途径中的任何过程都可能导致细胞改变。首先，NCOA4 在癌症治疗中发挥作用。研究表明，脂多糖（LPS）可以通过抑制NCOA4来调节铁蛋白转化，作为癌症的治疗靶点。 83 ]。粉防己碱柠檬酸盐（TetC）是一种新型高水溶性粉状放线菌酮盐，不仅对慢性粒细胞白血病具有很强的抗癌活性，而且对乳腺癌细胞也具有很强的抗癌活性，通过抑制GPX4的表达和NCOA4的激活，促进癌细胞中铁蛋白的自噬，从而诱导铁生成细胞死亡[ 80 ]。此外，其他途径已在铁蛋白自噬介导的癌症治疗中得到验证。例如，铁蛋白吞噬过程中铁通过溶酶体转运到线粒体的过程可以作为提高胰腺癌存活率和克服治疗耐药性的潜在靶标。 84 ]。铁蛋白吞噬产生的活性氧（ROS）可以激活p53和PHD2/HIF-1α信号通路，同时抑制铁螯合剂2,2'-二吡啶酮腙二硫代氨基甲酸酯s-丁酸（DpdtbA），从而诱导EMT在胃癌细胞中[ 85 ]。在依赖铁蛋白自噬的癌细胞中施用溴结构域蛋白 BRD4 抑制剂 (+)-JQ1 会触发铁死亡过程。因此，用 JQ1 处理的癌细胞表现出 LC3II/LC3I 比率增加、FTH1 表达减少以及自噬相关基因 ATG5 和 ATG7 表达减少。 86 ]。 以上表明越来越多的铁蛋白自噬相关分子正在成为癌症治疗的靶标。

Therapeutic mechanisms for common anticancer drugs have also been found in the ferritinophagy pathway. Low-dose cisplatin combined with ursolic acid inhibits cancer cell growth by activating autophagic degradation of ferritin and overloading intracellular iron ions [87]. Heavy floor saponin formosaninC (FC) induces ROS formation and GPX4 damage, promoting ferroptosis and ferritinophagy in triple-negative breast cancer MDA-MB-231 cells and increasing their chemosensitivity to cisplatin [88]. The combination of artesunate and hepatocellular carcinoma advanced first-line drug sorafenib induces oxidative stress and ferritinophagy in hepatocellular carcinoma cells and promotes lysosome-dependent FTL degradation to improve the efficacy of single drug [89]. Clinically, we need to know not only the drug efficacy, but also the adverse effects and the conditions of application of each drug to avoid additional serious damage to patients body. Rifampicin, the most common causative agent of antituberculosis drug-induced liver injury (AT-DILI), can reduce the hepatotoxicity of rifampicin by activating the autophagic pathway to reduce ferritinophagy and ferroptosis [90]. Additionally, the anticancer antibiotic Adriamycin was observed to enhance ferritinophagy by affecting the SPATA2/CYLD pathway, leading to NCOA4 depletion and ferroptosis induction in cardiomyocytes [91]. Carboplatin, a first-line drug for the treatment of human retinoblastoma (RB), develops acquired multidrug resistance (MDR) after long-term treatment, and its resistant mechanism can be eliminated by inducing autophagy-dependent ferroptosis [92]. In addition, it has also been recognized that the same drug efficacy can be exerted through multiple pathways. Dihydroartemisinin, a derivative of artemisinin, has been shown to have cytotoxic effects on a variety of malignant cancer cells of human origin, which can induce ferritinophagy and lysosomal degradation resulting in cell death in an autophagy-independent manner [93].
常见抗癌药物的治疗机制也在铁蛋白自噬途径中被发现。小剂量顺铂联合熊果酸通过激活铁蛋白自噬降解和细胞内铁离子超载抑制癌细胞生长。 87 ]。重地板皂苷 formosaninC (FC) 诱导 ROS 形成和 GPX4 损伤，促进三阴性乳腺癌 MDA-MB-231 细胞的铁死亡和铁蛋白自噬，并增加其对顺铂的化学敏感性。 88 ]。青蒿琥酯与肝细胞癌先进一线药物索拉非尼联用，诱导肝细胞癌细胞氧化应激和铁蛋白自噬，促进溶酶体依赖性FTL降解，提高单药疗效。 89 ]。临床上，我们不仅需要了解药物的疗效，还需要了解每种药物的不良反应以及使用条件，避免对患者身体造成额外的严重损害。利福平是抗结核药物性肝损伤（AT-DILI）最常见的致病因子，可通过激活自噬途径减少铁蛋白自噬和铁死亡，从而降低利福平的肝毒性。 90 ]。此外，抗癌抗生素阿霉素被观察到通过影响 SPATA2/CYLD 通路来增强铁蛋白自噬，导致心肌细胞中 NCOA4 耗竭和铁死亡诱导。 91 ]。卡铂是治疗人视网膜母细胞瘤（RB）的一线药物，长期治疗后会产生获得性多药耐药（MDR），其耐药机制可通过诱导自噬依赖性铁死亡来消除。 92 ]。此外，人们还认识到，相同的药物功效可以通过多种途径发挥出来。 双氢青蒿素是青蒿素的衍生物，已被证明对多种人类来源的恶性癌细胞具有细胞毒作用，可以诱导铁蛋白自噬和溶酶体降解，从而以不依赖自噬的方式导致细胞死亡。 93 ]。

Nanomaterials and photodynamic therapy acts anti-cancer effect by targeting ferritinophagy
纳米材料和光动力疗法通过靶向铁蛋白吞噬发挥抗癌作用

Nanomaterials have emerged as a valuable tool in the field of cancer treatment, particularly through their ability to modulate the ferritinophagy pathway. For instance, MoS2 nanosheets have been found to induce ferroptosis by degrading ferritin within the lysosome and inhibiting the function of recombinant FPN via NCOA4-dependent [94]. Moreover, nanomaterial-based systems have also been shown to connect ferritinophagy with the anticancer effects of the immune system. In this context, Zinc oxide nanoparticles exhibit promising biomedical applications by leveraging microautophagy/autophagy to induce ferroptosis in human umbilical vein endothelial cells, leading to vascular inflammation and ferritinophagy [95].
纳米材料已成为癌症治疗领域的宝贵工具，特别是通过其调节铁蛋白吞噬途径的能力。例如，MoS2 纳米片被发现可通过降解溶酶体内的铁蛋白并通过 NCOA4 依赖性抑制重组 FPN 的功能来诱导铁死亡。 94 ]。此外，基于纳米材料的系统也被证明可以将铁蛋白自噬与免疫系统的抗癌作用联系起来。在这种背景下，氧化锌纳米粒子通过利用微自噬/自噬诱导人脐静脉内皮细胞铁死亡，导致血管炎症和铁蛋白自噬，从而展现出有前景的生物医学应用。 95 ]。

In addition to common pharmacological treatments, photodynamic therapy (PDT) has established a new targeted therapeutic approach for osteosarcoma. PDT can promote ferroptosis in human osteosarcoma cells through NCOA4-mediated ferritinophagy and GPX4 inactivation, synergistic over-accumulation of lipid peroxides (LPOs), and significant induction of cytochrome c-activated mitochondrial apoptosis [96]. Immunity is closely related to cancers and activation of the immune system can also co-mediate cancer therapy with activation of ferritinophagy [97]. PDT-mediated activation of T cells and ferroptosis activation are connected, suggesting a theoretical basis for a new paradigm of cancer therapy [98]. Related studies have confirmed that increased ferroptosis can also promote the anticancer effects of immunotherapy. For instance, testosterone has been found to have a significant impact on prostate cancer, as supraphysiological levels of testosterone can impede the growth of prostate cells through ferritinophagy and nuclear autophagy. Additionally, it activates immune signaling pathways driven by nucleic acid sensors, leading to an increased migration of cytotoxic immune cells to the cancer site [99].
除了常见的药物治疗外，光动力疗法（PDT）为骨肉瘤建立了新的靶向治疗方法。 PDT 可通过 NCOA4 介导的铁蛋白自噬和 GPX4 失活、脂质过氧化物 (LPO) 的协同过度积累以及显着诱导细胞色素 c 激活的线粒体凋亡来促进人骨肉瘤细胞的铁死亡。 96 ]。免疫与癌症密切相关，免疫系统的激活也可以与铁蛋白自噬的激活共同介导癌症治疗。 97 ]。 PDT 介导的 T 细胞激活和铁死亡激活是相关的，这为癌症治疗的新范式提供了理论基础。 98 ]。相关研究证实，铁死亡增加也能促进免疫疗法的抗癌作用。例如，睾酮已被发现对前列腺癌有显着影响，因为超生理水平的睾酮可通过铁蛋白自噬和核自噬阻碍前列腺细胞的生长。此外，它还激活由核酸传感器驱动的免疫信号通路，导致细胞毒性免疫细胞向癌症部位的迁移增加。 99 ]。

Immunity plays an anti-cancer role by targeting ferritinophagy
免疫通过靶向铁蛋白吞噬发挥抗癌作用

The human immune system has the role of immune surveillance, defense and regulation, which is closely related to the occurrence and development of cancers. When the immune function of body decreases, the cancer is easy to invade, so the cancer immunity can be used to study the occurrence, development and regression of cancers [100]. Furthermore, the search for cancer markers remains an ongoing and extensive endeavor. The emergence of new antigenic markers for cancer cells is a prominent immunological feature of cancer cells [101], and the release of inflammatory factors by the immune system stimulated by ferritinophagy death cells [7] provides us with good direction. Immune checkpoint blockade is a powerful oncologi inflammatory factors treatment modality for a wide range of human malignancies [102], and targeting the cancer ferritinophagy pathway might be an immune checkpoint blockade therapy. Preclinical data suggest that immune checkpoint blockade can act synergistically with radiotherapy through agonism of innate immune sensing pathways activated by DNA damage [103]. Notably, two separate studies have concurrently demonstrated that immunotherapy-activated CD8+ T cells augment lipid peroxidation in ferroptosis cancer cells. Furthermore, it has been observed that heightened ferroptosis contributes to the effectiveness of immunotherapy in combating cancer [104, 105]. In addition, the reduction in iron and FTH due to ferroptosis inhibition impedes dendritic cell-mediated anticancer immunity and therefore may interfere with immunotherapy [106, 107]. How the induction of ferroptosis through ferritinophagy modulates immune efficacy is still unknown, and the mechanisms controlling the immune response to specific ferritinophagy remain poorly defined. A current challenge in oncology is to effectively integrate immunotherapy with conventional therapies, involved radiotherapy. Recent years have provided insights into the molecular mechanisms [108], pharmacological regulation [109] and functional significance of ferritinophagy in health and disease [110]. However, the mediators of its immune response elicitation remain poorly defined. Immunogenic cell death is an important factor in the success of anticancer therapy [111]. Although it is promising that the application of the ferritinophagy pathway to therapy, how ferritinophagy works with the immune system to fight cancer cell processes remains unclear.
人体免疫系统具有免疫监视、防御和调节作用，与癌症的发生、发展密切相关。当机体免疫功能下降时，癌症就容易侵袭，因此可以利用癌症免疫来研究癌症的发生、发展和消退。 100 ]。此外，对癌症标志物的寻找仍然是一项持续且广泛的努力。癌细胞新抗原标记的出现是癌细胞的一个突出的免疫学特征。 101 ]，以及铁蛋白吞噬死亡细胞刺激的免疫系统释放炎症因子[ 7 ] 为我们提供了良好的方向。免疫检查点阻断是一种针对多种人类恶性肿瘤的强大的肿瘤炎症因子治疗方式。 102 ]，针对癌症铁蛋白吞噬途径可能是一种免疫检查点阻断疗法。临床前数据表明，免疫检查点阻断可以通过 DNA 损伤激活的先天免疫传感途径的激动作用与放射治疗产生协同作用。 103 ]。值得注意的是，两项独立的研究同时证明，免疫疗法激活的 CD8+ T 细胞会增强铁死亡癌细胞中的脂质过氧化作用。此外，据观察，铁死亡的加剧有助于免疫疗法对抗癌症的有效性。 104 , 105 ]。此外，铁死亡抑制导致铁和 FTH 的减少会阻碍树突状细胞介导的抗癌免疫，因此可能会干扰免疫治疗。 106 , 107 ]。 通过铁蛋白自噬诱导铁死亡如何调节免疫功效仍不清楚，并且控制对特定铁蛋白自噬的免疫反应的机制仍不清楚。肿瘤学当前的挑战是将免疫疗法与传统疗法（包括放射疗法）有效整合。近年来，人们对分子机制有了深入的了解[ 108 ]、药理调节[ 109 ] 铁蛋白自噬在健康和疾病中的功能意义 [ 110 ]。然而，其免疫反应引发的介质仍然不明确。免疫原性细胞死亡是抗癌治疗成功的重要因素[ 111 ]。尽管铁蛋白自噬途径在治疗中的应用前景广阔，但铁蛋白自噬如何与免疫系统一起对抗癌细胞过程仍不清楚。