铁死亡机制及其在肿瘤治疗中的应用

铁死亡作为新发现的一种调节性细胞死亡,是一类铁依赖性脂质过氧化物累积所导致的细胞死亡方式。铁死亡与铁离子代谢、脂质代谢和氨基酸代谢存在密切关联。随着铁死亡相关分子机制的不断发展和完善,铁死亡在肿瘤治疗方面表现出良好的应用前景。本文将介绍铁死亡机制的研究进展及其在肿瘤治疗中的应用探索。     

Double-edge sword roles of iron in driving energy production versus instigating ferroptosis

Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.Subject terms: Cell biology, Biochemistry     

Mitochondria regulation in ferroptosis

Ferroptosis is recognized as a new form of regulated cell death which is initiated by severe lipid peroxidation relying on reactive oxygen species (ROS) generation and iron overload. This iron-dependent cell death manifests evident morphological, biochemical and genetic differences from other forms of regulated cell death, such as apoptosis, autophagy, necrosis and pyroptosis. Ferroptosis was primarily characterized by condensed mitochondrial membrane densities and smaller volume than normal mitochondria, as well as the diminished or vanished of mitochondria crista and outer membrane ruptured. Mitochondria take the center role in iron metabolism, as well as substance and energy metabolism as it’s the major organelle in iron utilization, catabolic and anabolic pathways. Interference of key regulators of mitochondrial lipid metabolism (e.g., ASCF2 and CS), iron homeostasis (e.g., ferritin, mitoferrin1/2 and NEET proteins), glutamine metabolism and other signaling pathways make a difference to ferroptotic sensitivity. Targeted induction of ferroptosis was also considered as a potential therapeutic strategy to some oxidative stress diseases, including neurodegenerative disorders, ischemia-reperfusion injury, traumatic spinal cord injury. However, the pertinence between mitochondria and ferroptosis is still in dispute. Here we systematic elucidate the morphological characteristics and metabolic regulation of mitochondria in the regulation of ferroptosis.     

泛素化在调控铁死亡中的作用

铁死亡是一种由脂质过氧化驱动的铁依赖性的新的细胞死亡方式,越来越多的证据表明,铁死亡与各种病理状态有关,如神经退行性疾病、糖尿病肾病、癌症等,脂质过氧化驱动的铁死亡可能促进或抑制这些疾病的发生发展,细胞中抗氧化系统通过抑制脂质过氧化在抵抗铁死亡过程中发挥着重要作用。铁死亡的关键通路有以SLC7A11-GPX4为关键分子的氨基酸代谢通路、以铁蛋白或转铁蛋白为主的铁代谢通路,以及脂质代谢通路。铁死亡的发生受到细胞内蛋白质的调节,这些蛋白质会发生各种翻译后修饰,包括泛素化修饰。泛素-蛋白酶体系统（ubiquitin-proteasome system,UPS）是细胞内主要降解系统之一,通过酶促级联反应催化泛素分子标记待降解蛋白,随后由蛋白酶体识别并降解目标蛋白质。UPS根据其降解底物的不同在调节铁死亡的反应中发挥双重作用。UPS通过促进铁死亡关键分子（如SLC7A11、GPX4、GSH）以及抗氧化系统成分（如NRF2）的泛素化降解从而促进铁死亡,也可以通过促进脂质代谢通路中相关分子（如ACSL4、ALOX15）的泛素化降解从而抑制铁死亡。本综述介绍泛素化修饰在调控铁死亡进程中作用的最新研究进展,总结了已发表的关于E3泛素连接酶和去泛素酶调控铁死亡的研究,归纳了泛素连接酶、去泛素酶调控铁死亡的作用靶点,有助于确定人类疾病中新的预后指标,为这些疾病提供潜在的治疗策略。     

Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology

Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer''s disease, Parkinson''s disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment.     

铁死亡与肾脏疾病相关性的研究进展

铁死亡(ferroptosis)是2012年新发现的一种非凋亡的细胞死亡形式,其实质是依赖铁离子的活性氧(reactive oxygen species,ROS)和脂质氢过氧化物蓄积导致的线粒体形态改变和细胞膜磷脂过氧化损伤。铁死亡与许多肾脏疾病的病理生理进程密切相关。然而铁死亡参与肾脏疾病损伤的分子生物学机制尚缺乏系统和深入的认识。针对铁死亡的调控机制、研究进展及其在肾脏相关疾病中的作用作一综述,以期为肾脏疾病的治疗提供新思路、新靶点。     

Ferroptosis: Final destination for cancer?

Ferroptosis is a recently defined, non‐apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron‐containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy‐dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.     

铁死亡发生机制的研究进展

铁死亡(ferroptosis)是近几年发现的一种新的细胞死亡方式,是在小分子物质诱导下发生的氧化性细胞死亡,具有铁离子依赖性.其发生是细胞内脂质活性氧(reactive oxygen species,ROS)生成与降解的平衡失调所致.铁死亡诱导剂通过不同的通路直接或间接作用于谷胱甘肽过氧化物酶(glutathione peroxidase,GPXs),导致细胞抗氧化能力降低、ROS堆积、最终引起细胞氧化性死亡.铁死亡与帕金森综合征、胰腺癌等多种疾病相关,并发现可以通过激活或抑制铁死亡来干预疾病的发展,因此铁死亡成为近年来的研究热点.本文就铁死亡的发现、特点、发生机制及其与疾病的关系展开论述,将近年研究成果进行总结,期望为以铁死亡为基础的疾病治疗提供参考.     

铁死亡的生化过程及对肿瘤的影响

铁死亡(ferroptosis）是近年提出的一种调节性细胞死亡方式,主要依赖于细胞内铁和脂质活性氧（reactive oxygen species, ROS）积累所引起的细胞死亡。铁死亡的发生与多种生物化学过程密切相关,包括多不饱和脂肪酸、铁和氨基酸代谢,以及谷胱甘肽、磷脂、烟酰胺腺嘌呤二核苷酸磷酸（nicotinamide adenine dinucleotide phosphate, NADPH）和辅酶Q10的生物合成。与正常细胞相比,肿瘤细胞内ROS水平通常较高,因而与ROS有关的铁死亡对肿瘤疾病的影响引人注目。在调节肿瘤细胞如卵巢恶性肿瘤、头颈部癌、弥漫性大B细胞淋巴瘤、肝癌,以及横纹肌肉瘤的生长和增殖中,铁死亡发挥了不可忽视的作用。本文主要阐述了各种生物化学过程对铁死亡的影响,以及铁死亡在肿瘤疾病中的研究进展,为肿瘤疾病的治疗提供新思路。     

NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury

Oxidative stress and lipid peroxidation are major causes of skin injury induced by ultraviolet (UV) irradiation. Ferroptosis is a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids and contributes to kinds of tissue injuries. However, it remains unclear whether the accumulation of lipid peroxides in UV irradiation-induced skin injury could lead to ferroptosis. We generated UV irradiation-induced skin injury mice model to examine the accumulation of the lipid peroxides and iron. Lipid peroxides 4-HNE, the oxidative enzyme COX2, the oxidative DNA damage biomarker 8-OHdG, and the iron level were increased in UV irradiation-induced skin. The accumulation of iron and lipid peroxidation was also observed in UVB-irradiated epidermal keratinocytes without actual ongoing ferroptotic cell death. Ferroptosis was triggered in UV-irradiated keratinocytes stimulated with ferric ammonium citrate (FAC) to mimic the iron overload. Although GPX4 protected UVB-injured keratinocytes against ferroptotic cell death resulted from dysregulation of iron metabolism and the subsequent increase of lipid ROS, keratinocytes enduring constant UVB treatment were markedly sensitized to ferroptosis. Nicotinamide mononucleotide (NMN) which is a direct and potent NAD⁺ precursor supplement, rescued the imbalanced NAD⁺/NADH ratio, recruited the production of GSH and promoted resistance to lipid peroxidation in a GPX4-dependent manner. Taken together, our data suggest that NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation-induced skin injury and inhibits oxidative skin damage. NMN or ferroptosis inhibitor might become promising therapeutic approaches for treating oxidative stress-induced skin diseases or disorders.     

Iron deposition-induced ferroptosis in alveolar type II cells promotes the development of pulmonary fibrosis

Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in numerous human diseases. However, its role in pulmonary fibrosis, a fatal lung disease with unknown etiology, is largely unknown. Here, we investigated the role of ferroptosis in pulmonary fibrosis. We found a large amount of iron deposition in the lung tissue of patients with pulmonary fibrosis. We observed ferroptosis in alveolar type II (ATII) cells, fibrotic lung tissues of BLM-induced pulmonary fibrosis mice. BLM-induced increase in iron level was accompanied by pathological changes, collagen deposition, and ferroptosis in ATII cells, indicating iron deposition-induced ferroptosis, which promoted the development of pulmonary fibrosis. Moreover, deferoxamine (DFO) completely prevented the pro-fibrosis effects of BLM by reducing iron deposition and ferroptosis in ATII cells. Genes associated with intracellular iron metabolism and homeostasis, such as transferrin receptor 1, divalent metal transporter 1, and ferroportin-1, and showed abnormal expression levels in animal tissues and lung epithelial MLE-12 cells, which responded to BLM stimulation. Overall, we demonstrated that BLM-induced iron deposition in MLE-12 cells is prone to both mitochondrial dysfunction and ferroptosis and that DFO reverses this phenotype. In the future, understanding the role of ferroptosis may shed new light on the etiology of pulmonary fibrosis. Ferroptosis inhibitors or genetic engineering of ferroptosis-related genes might offer potential targets to treat pulmonary fibrosis.     

Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells

Ferroptosis is a regulated form of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Ceruloplasmin (CP) is a glycoprotein that plays an essential role in iron homeostasis. However, whether CP regulates ferroptosis has not been reported. Here, we show that CP suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma (HCC) cells. Depletion of CP promoted erastin- and RSL3-induced ferroptotic cell death and resulted in the accumulation of intracellular ferrous iron (Fe²⁺) and lipid reactive oxygen species (ROS). Moreover, overexpression of CP suppressed erastin- and RSL3-induced ferroptosis in HCC cells. In addition, a novel frameshift mutation (c.1192-1196del, p.leu398serfs) of CP gene newly identified in patients with iron accumulation and neurodegenerative diseases lost its ability to regulate iron homeostasis and thus failed to participate in the regulation of ferroptosis. Collectively, these data suggest that CP plays an indispensable role in ferroptosis by regulating iron metabolism and indicate a potential therapeutic approach for hepatocellular carcinoma.     

Interaction between macrophages and ferroptosis

AbstractFerroptosis, a newly discovered iron-dependent cell death pathway, is characterized by lipid peroxidation and GSH depletion mediated by iron metabolism and is morphologically, biologically and genetically different from other programmed cell deaths. Besides, ferroptosis is usually found accompanied by inflammatory reactions. So far, it has been found participating in the development of many kinds of diseases. Macrophages are a group of immune cells that widely exist in our body for host defense and play an important role in tissue homeostasis by mediating inflammation and regulating iron, lipid and amino acid metabolisms through their unique functions like phagocytosis and efferocytosis, cytokines secretion and ROS production under different polarization. According to these common points in ferroptosis characteristics and macrophages functions, it’s obvious that there must be relationship between macrophages and ferroptosis. Therefore, our review aims at revealing the interaction between macrophages and ferroptosis concerning three metabolisms and integrating the application of certain relationship in curing diseases, mostly cancer. Finally, we also provide inspirations for further studies in therapy for some diseases by targeting certain resident macrophages in distinct tissues to regulate ferroptosis.Facts

• Ferroptosis is considered as a newly discovered form characterized by its nonapoptotic and iron-dependent lipid hydroperoxide, concerning iron, lipid and amino acid metabolisms.
• Ferroptosis has been widely found playing a crucial part in various diseases, including hepatic diseases, neurological diseases, cancer, etc.
• Macrophages are phagocytic immune cells, widely existing and owning various functions such as phagocytosis and efferocytosis, cytokines secretion and ROS production.
• Macrophages are proved to participate in mediating metabolisms and initiating immune reactions to maintain balance in our body.
• Recent studies try to treat cancer by altering macrophages’ polarization which damages tumor microenvironment and induces ferroptosis of cancer cells.

Open questions

• How do macrophages regulate ferroptosis of other tissue cells specifically?
• Can we use the interaction between macrophages and ferroptosis in treating diseases other than cancer?
• What can we do to treat diseases related to ferroptosis by targeting macrophages?
• Is the use of the relationship between macrophages and ferroptosis more effective than other therapies when treating diseases?

Subject terms: Cell death and immune response, Cytokines, Cancer immunotherapy     

The multifaceted role of ferroptosis in liver disease

Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora of pathological conditions in the liver. Emerging evidence supports the notion that dysregulated metabolic pathways and impaired iron homeostasis play a role in the progression of liver disease via ferroptosis. Although the molecular mechanisms by which ferroptosis causes disease are poorly understood, several ferroptosis-associated genes and pathways have been implicated in liver disease. Here, we review the physiological role of the liver in processing nutrients, our current understanding of iron metabolism, the characteristics of ferroptosis, and the mechanisms that regulate ferroptosis. In addition, we summarize the role of ferroptosis in the pathogenesis of liver disease, including liver injury, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Finally, we discuss the therapeutic potential of targeting ferroptosis for managing liver disease.Subject terms: Translational research, Autophagy, Experimental models of disease     

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System X_c(−) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.Subject terms: Cancer metabolism, Cell death     

自噬和铁死亡的相互联系

自噬是一个保守的细胞内降解系统,在细胞死亡中起着双重作用,可以为细胞在营养缺乏条件下提供一些必要的营养物质促进细胞存活,但是自噬过度发生会导致细胞内一些正常组分被降解从而加速细胞死亡.铁死亡是一种新的细胞死亡调控形式,主要依赖于铁的积累和脂质过氧化.铁死亡在细胞形态、生物化学特征和所涉及的调控因子上都与自噬以及其他类型...     

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron‐dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.     

Ferroptosis: Role of lipid peroxidation,iron and ferritinophagy

Ferroptosis is a form of regulated cell death that is dependent on iron and reactive oxygen species (ROS) and is characterized by lipid peroxidation. It is morphologically and biochemically distinct and disparate from other processes of cell death. As ferroptosis is induced by inhibition of cysteine uptake or inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4), the process is favored by chemical or mutational inhibition of the cystine/glutamate antiporter and culminates in the accumulation of reactive oxygen species (ROS) in the form of lipid hydroperoxides. Excessive lipid peroxidation leads to death by ferroptosis and the phenotype is accentuated respectively by the repletion and depletion of iron and glutathione in cells. Furthermore, oxidized phosphatidylethanolamines (PE) harbouring arachidonoyl (AA) and adrenoyl moieties (AdA) have been shown as proximate executioners of ferroptosis. Induction of ferroptosis due to cysteine depletion leads to the degradation of ferritin (i.e. ferritinophagy), which releases iron via the NCOA4-mediated autophagy pathway. Evidence of the manifestation of ferroptosis in vivo in iron overload mice mutants is emerging. Thus, a concerted synchronization of iron availability, ROS generation, glutamate excess and cysteine deficit leads to ferroptosis. A number of questions on the molecular mechanisms of some features of ferroptosis are highlighted as subjects for future investigations.     

A tale of two lipids: Lipid unsaturation commands ferroptosis sensitivity

Membrane lipids play important roles in the regulation of cell fate, including the execution of ferroptosis. Ferroptosis is a non-apoptotic cell death mechanism defined by iron-dependent membrane lipid peroxidation. Phospholipids containing polyunsaturated fatty acids (PUFAs) are highly vulnerable to peroxidation and are essential for ferroptosis execution. By contrast, the incorporation of less oxidizable monounsaturated fatty acids (MUFAs) in membrane phospholipids protects cells from ferroptosis. The enzymes and pathways that govern PUFA and MUFA metabolism therefore play a critical role in determining cellular sensitivity to ferroptosis. Here, we review three lipid metabolic processes—fatty acid biosynthesis, ether lipid biosynthesis, and phospholipid remodeling—that can govern ferroptosis sensitivity by regulating the balance of PUFAs and MUFAs in membrane phospholipids.