Ferroptosis and its interaction with tumor immune microenvironment in liver cancer

Exploring effective systemic treatments for liver cancer is still a great challenge worldwide. As a novel form of regulated cell death, ferroptosis has been paid more and more attention in the cancer research field. In recent years, targeting ferroptosis has become an encouraging strategy for liver cancer treatment. Cancer cells can be directly killed by inducing ferroptosis; in contrast, ferroptosis can also ameliorate the tumor immunosuppressive microenvironment and sensitize cancers to immunotherapy. Here, we summarize fully current progress in the iron homeostasis in the liver, the internal association between imbalanced iron homeostasis and ferroptosis in liver carcinogenesis and development, as well as ferroptosis-related regulators in liver cancer. Furthermore, we discuss thoroughly the interaction between ferroptosis and tumor immune microenvironment. Finally, we provide certainly a future insight on the potential value of ferroptosis in the immunotherapy of liver cancer.     

Close interactions between lncRNAs,lipid metabolism and ferroptosis in cancer

Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabolism and ferroptosis in cancer. In this review, we mainly summarized the mechanism by which lncRNAs regulate aberrant lipid metabolism in cancer, illustrated that lipid metabolism can also influence the expression of lncRNAs, and discussed the mechanism by which lncRNAs affect ferroptosis. A comprehensive understanding of the interactions between lncRNAs, lipid metabolism and ferroptosis could help us to develop novel strategies for precise cancer treatment in the future.     

Vitamin D may alleviate pre-eclampsia by modulating the ferroptosis signalling pathway: A hypothesis based on recent literature

Ferroptosis is a novel form of regulated cell death typically characterized by non-apoptotic, iron-dependent, and reactive accumulation of oxygen species. Recent studies have found that ferroptosis plays an important role in the pathophysiology of pre-eclampsia (PE). In order to find potential therapeutic targets for ferroptosis intervention and better prevent the occurrence and progression of PE, the signalling pathways that regulate ferroptosis need to be identified. In this article, we review the role of vitamin D in PE and the role of ferroptosis in PE. Based on recent literature, we propose the scientific hypothesis that vitamin D can alleviate preeclampsia by modulating the ferroptosis signalling pathway. The aim of this review is to understand the regulatory pathways of ferroptosis in PE and to identify potential therapeutic targets.     

The role of ferroptosis in melanoma

Melanoma is the deadliest form of skin cancer. Although treatment with targeted therapies and immune checkpoint inhibitors has dramatically improved survival in advanced melanoma, many patients do not benefit from these therapies or relapse after an initial period of response. Thus, future outcomes in these categories of melanoma patients will depend on the identification of novel therapeutic targets and methods to enhance existing targeted therapy and immunotherapy regimens. Ferroptosis is a newly identified form of iron-dependent regulated cell death that is morphologically, biochemically, and genetically distinct from apoptosis, autophagy, pyroptosis, and necroptosis. Dysregulation of ferroptosis has been linked to the development of several forms of cancer. This review examines ferroptosis in the context of melanoma. It presents an overview of ferroptosis biology, summarizes and interprets the current literature, and poses several outstanding questions and areas of future direction.     

Mitochondria bridge HIF signaling and ferroptosis blockage in acute kidney injury

Ferroptosis, a form of regulated cell death, plays an important role in acute kidney injury (AKI). Previous studies have shown that prolyl hydroxylase domain protein (PHD) inhibitors that activate HIF signaling provide strong protection against AKI, which is characterized by marked cell death. However, the relationship between PHD inhibition/HIF signaling and ferroptosis in AKI has not been elucidated. Here, we review recent studies to explore the issue. First, we will review the literature concerning the functions of HIF in promoting mitophagy, suppressing mitochondrial respiration and modulating redox homeostasis. Second, we will describe the current understanding of ferroptosis and its role in AKI, particularly from the perspective of mitochondrial dysfunction. Finally, we will discuss the possibility that mitochondria link PHD inhibition/HIF signaling and ferroptosis in AKI. In conclusion, we propose that HIF may protect renal cells against ferroptosis in AKI by reducing mitochondrial oxidative stress and damage.Subject terms: Cell biology, Kidney diseases     

肿瘤细胞死亡的一种新形式——铁死亡

铁死亡是近年来发现的一种程序性细胞死亡新形式,其主要特征是在发生于线粒体内的铁依赖性脂质过氧化物损伤诱导的细胞死亡。铁死亡细胞在形态、蛋白质及基因水平的变化均不同于细胞凋亡、坏死和自噬。2012年,铁死亡概念首次被提出后,铁死亡逐渐成为科学研究的热点。Erastin以及RSL3是铁死亡的诱导剂,谷胱甘肽过氧化物酶4（glutathione peroxidase 4,GPX4）是铁死亡的关键调节点,GPX4的表达量减少或活性降低均可诱导铁死亡的发生。胱氨酸-谷氨酸逆向转运蛋白（system Xc^-）可将细胞内的谷氨酸排出,同时将细胞外胱氨酸转运入细胞内,促进细胞内谷胱甘肽的合成,维持GPX4酶的活性。新近的研究表明,p62-keap1-Nrf2、P53-SAT1-ALOX15是铁死亡的关键调控通路,p53、BECN1以及BAP1是铁死亡的关键调节因子。Erastin以及RSL3可以选择性杀死RAS突变的肿瘤细胞,且越来越多的研究也证明,诱导肿瘤细胞铁死亡在免疫治疗以及逆转耐药方面均有着重要作用。因此,调控肿瘤细胞铁死亡很可能成为治疗肿瘤的新手段。本文就诱导肿瘤细胞铁死亡的机制及其进展作一综述。     

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...     

Crosstalk between ferroptosis and the epithelial-mesenchymal transition: Implications for inflammation and cancer therapy

Both genomic instability and the presence of chronic inflammation are involved in carcinogenesis and tumor progression. These alterations predispose the cancer cells to undergo metabolic reprogramming as well as the epithelial-mesenchymal transition (EMT). These pathways allow cancer cells to avoid apoptosis and stimulate tumor progression. EMT is an important early event in tumor cell invasion, which can be regulated through inflammatory signaling pathways. Cancer cells undergoing EMT are vulnerable to cell death by the process of ferroptosis. Ferroptosis is a form of regulated cell death involving iron-dependent lipid peroxidation, designed to maintain cellular homeostasis. Several reports have linked ferroptosis, inflammation, and cancer. Ferroptosis inhibitors and EMT inducers have been used to understand the anti-inflammatory and anticancer effects in experimental models. A better understanding of the crosstalk between ferroptosis and EMT, and the involvment of inflammatory mediators may accelerate the discovery of therapeutic strategies to eradicate cancer cells and overcome drug-resistance.     

肿瘤细胞死亡的一种新形式——铁死亡

铁死亡是近年来发现的一种程序性细胞死亡新形式,其主要特征是在发生于线粒体内的铁依赖性脂质过氧化物损伤诱导的细胞死亡。铁死亡细胞在形态、蛋白质及基因水平的变化均不同于细胞凋亡、坏死和自噬。2012年,铁死亡概念首次被提出后,铁死亡逐渐成为科学研究的热点。Erastin以及RSL3是铁死亡的诱导剂,谷胱甘肽过氧化物酶4（glutathione peroxidase 4,GPX4）是铁死亡的关键调节点,GPX4的表达量减少或活性降低均可诱导铁死亡的发生。胱氨酸-谷氨酸逆向转运蛋白（system Xc^-）可将细胞内的谷氨酸排出,同时将细胞外胱氨酸转运入细胞内,促进细胞内谷胱甘肽的合成,维持GPX4酶的活性。新近的研究表明,p62-keap1-Nrf2、P53-SAT1-ALOX15是铁死亡的关键调控通路,p53、BECN1以及BAP1是铁死亡的关键调节因子。Erastin以及RSL3可以选择性杀死RAS突变的肿瘤细胞,且越来越多的研究也证明,诱导肿瘤细胞铁死亡在免疫治疗以及逆转耐药方面均有着重要作用。因此,调控肿瘤细胞铁死亡很可能成为治疗肿瘤的新手段。本文就诱导肿瘤细胞铁死亡的机制及其进展作一综述。     

Metabolic regulation of ferroptosis in the tumor microenvironment

Ferroptosis is an iron-dependent, nonapoptotic form of regulated cell death triggered by impaired redox and antioxidant machinery and propagated by the accumulation of toxic lipid peroxides. A compendium of experimental studies suggests that ferroptosis is tumor-suppressive. Sensitivity or resistance to ferroptosis can be regulated by cell-autonomous and non-cell-autonomous metabolic mechanisms. This includes a role for ferroptosis that extends beyond the tumor cells themselves, mediated by components of the tumor microenvironment, including T cells and other immune cells. Herein, we review the intrinsic and extrinsic factors that promote the sensitivity of cancer cells to ferroptosis and conclude by describing approaches to harness the full utility of ferroptotic agents as therapeutic options for cancer therapy.     

细胞铁死亡的形态学特征及相关疾病治疗

铁死亡是一种铁依赖的脂质过氧化产物积累引发的细胞死亡,与细胞凋亡、程序性坏死等同属受调控的细胞死亡方式,参与多种疾病的发生、发展,如脑卒中、神经退行性疾病、癌症等。通过调控铁死亡来干预疾病的发生发展,已成为目前研究的热点和焦点。大量研究表明,铁死亡与已知的其他细胞死亡类型在形态学方面存在着较大的差异。本文重点就铁死亡形态学特征与其他形式的细胞死亡进行比较,以期更加准确地认识铁死亡和其他形式的细胞死亡,为临床病理学鉴别、诊断提供重要依据。     

Multi-omics Analysis of Ferroptosis Regulation Patterns and Characterization of Tumor Microenvironment in Patients with Oral Squamous Cell Carcinoma

Ferroptosis is a newly recognized mechanism of regulated cell death. It was reported to be highly associated with immune therapy and chemotherapy. However, its mechanism of regulation in the tumor microenvironment (TME) and influence on oral squamous cell carcinoma (OSCC) therapy are unknown. We identified a ferroptosis-specific gene-expression signature, an FPscore, developed by a principal component analysis (PCA) algorithm to evaluate the ferroptosis regulation patterns of individual tumor. Multi-omics analysis of ferroptosis regulation patterns was conducted. Three distinct ferroptosis regulation subtypes, which linked to outcomes and the clinical relevance of each patient, were established. A high FPscore of patients with OSCC was associated with a favorable prognosis, a ferroptosis-related immune-activation phenotype, potential sensitivities to the chemotherapy and immunotherapy. Importantly, a high FPscore correlated with a low gene copy number burden and high immune checkpoint expressions. We validated the prognostic value of the FPscore using independent immunotherapy and pan-cancer cohorts. Comprehensive evaluation of individual tumors with distinct ferroptosis regulation patterns provides new mechanistic insights, which may be clinically relevant for the application of combination therapies in OSCC.     

Autophagy promotes ferroptosis by degradation of ferritin

Macroautophagy/autophagy is an evolutionarily conserved degradation pathway that maintains homeostasis. Ferroptosis, a novel form of regulated cell death, is characterized by a production of reactive oxygen species from accumulated iron and lipid peroxidation. However, the relationship between autophagy and ferroptosis at the genetic level remains unclear. Here, we demonstrated that autophagy contributes to ferroptosis by degradation of ferritin in fibroblasts and cancer cells. Knockout or knockdown of Atg5 (autophagy-related 5) and Atg7 limited erastin-induced ferroptosis with decreased intracellular ferrous iron levels, and lipid peroxidation. Remarkably, NCOA4 (nuclear receptor coactivator 4) was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis. Consistently, genetic inhibition of NCOA4 inhibited ferritin degradation and suppressed ferroptosis. In contrast, overexpression of NCOA4 increased ferritin degradation and promoted ferroptosis. These findings provide novel insight into the interplay between autophagy and regulated cell death.     

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。     

Lipid storage and lipophagy regulates ferroptosis

The synthesis, storage, and degradation of lipids are highly regulated processes. Impaired lipid metabolism is implicated in inflammation and cell death. Although ferroptosis is a recently described form of regulated cell death driven by lipid peroxidation, the impact of lipid droplets on ferroptosis remains unidentified. Here, we demonstrate that lipophagy, the autophagic degradation of intracellular lipid droplets, promotes RSL3-induced ferroptotic cell death in hepatocytes. Lipid droplet accumulation is increased at the early stage but decreased at the late stage of ferroptosis in mouse or human hepatocytes. Importantly, either genetically enhancing TPD52-dependent lipid storage or blocking ATG5-and RAB7A-dependent lipid degradation prevents RSL3-induced lipid peroxidation and subsequent ferroptosis in vitro and in vivo. These studies support an antioxidant role for lipid droplets in cell death and suggest novel strategies for the inhibition of ferroptosis by targeting the lipophagy pathway.     

Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

Ferroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca²⁺ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of a few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca²⁺ fluxes during ferroptosis induce the activation of the ESCRT-III-dependent membrane repair machinery, which counterbalances the kinetics of cell death and modulates the immunological signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained increase of cytosolic Ca²⁺ prior to plasma membrane rupture is a common feature of regulated types of necrosis and position ESCRT-III activation as a general protective mechanism in these lytic cell death pathways.Subject terms: Cell biology, Molecular biology     

基于铁死亡的抗结直肠癌药物的应用

结直肠癌（colorectal cancer，CRC）是癌症相关死亡的第二大主要原因，且患者趋于年轻化，化疗、免疫治疗及靶向治疗等药物治疗虽然取得进展，但因药物的毒性、耐药及价格昂贵严重影响CRC的综合治疗效果，因此寻求新的、更敏感有效的药物和药物靶点是目前研究的热点。铁死亡作为一种近期发现的细胞死亡调节方式，它与癌症药物耐药性、敏感性密切相关，激活铁死亡成为克服传统癌症治疗耐药机制的潜在策略，诱导铁死亡的药物研发应用有望成为治疗CRC的有效手段。本文综述在CRC中铁死亡相关代谢途径药物研究的最新进展，以便整体认识基于铁死亡的药物在CRC中作用的具体机制，充分发掘其治疗潜力，为CRC的诊疗和耐药性的解决提供新的思路。     

When ferroptosis meets pathogenic infections

Apoptosis, necrosis, or autophagy are diverse types of regulated cell death (RCD), recognized as the strategies that host cells use to defend against pathogens such as viruses, bacteria, or fungi. Pathogens can induce or block different types of host cell RCD, promoting propagation or evading host immune surveillance. Ferroptosis is a newly identified RCD. Evidence has demonstrated how pathogens regulate ferroptosis to promote their replication, dissemination, and pathogenesis. However, the interaction between ferroptosis and pathogenic infections still needs to be completely elucidated. This review summarizes the advances in the interaction between pathogenic infections and host ferroptotic processes, focusing on the underlying mechanisms of how pathogens exploit ferroptosis, and discussing possible therapeutic measures against pathogen-associated diseases in a ferroptosis-dependent manner.