Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous ...interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.
Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ...ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR- or KEAP1 deficiency-induced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.
Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to ...play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.
Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under ...specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers.
Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly ...inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively ...importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11
) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11
cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11
cancer cells and suppress SLC7A11
tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11
cancers.
Ferroptosis, a form of regulated cell death triggered by lipid hydroperoxide accumulation, has an important role in a variety of diseases and pathological conditions, such as cancer. Targeting ...ferroptosis is emerging as a promising means of therapeutic intervention in cancer treatment. Polyunsaturated fatty acids, reactive oxygen species, and labile iron constitute the major underlying triggers for ferroptosis. Other regulators of ferroptosis have also been discovered recently, among them the mechanistic target of rapamycin complex 1 (mTORC1), a central controller of cell growth and metabolism. Inhibitors of mTORC1 have been used in treating diverse diseases, including cancer. In this review, we discuss recent findings linking mTORC1 to ferroptosis, dissect mechanisms underlying the establishment of mTORC1 as a key ferroptosis modulator, and highlight the potential of co‐targeting mTORC1 and ferroptosis in cancer treatment. This review will provide valuable insights for future investigations of ferroptosis and mTORC1 in fundamental biology and cancer therapy.
mTORC1 protecting against ferroptosis: SLC7A11‐mediated cystine uptake and the PI3K/AKT signaling promote mTORC1 activation, which promotes GPX4 protein synthesis by inhibiting downstream 4EBPs, enhances MUFA synthesis by upregulating the SREBP1‐SCD1 axis, and inhibits autophagy, thereby suppressing lipid peroxidation and ferroptosis.
Abstract
Various wet‐laid nonwoven composites have been well‐developed in recent decades. However, studies that systematically investigate the factors affecting the void content of wet‐laid nonwoven ...composites are still missing. This paper aims to study the factors affecting the void content of wet‐laid nonwoven composites and propose a mechanism for void elimination in wet‐laid nonwoven composites. Polypropylene (PP) and carbon fiber (CF) were chosen to manufacture PP/CF wet‐laid nonwoven composites. An orthogonal experimental design found that the CF content and molding pressure can dominate the void content while molding temperature and time have non‐significant effects. Subsequently, this paper proposed that the void elimination mechanism is the compression of the impregnated CF network and the trapped air (compression mechanism) instead of the matrix's infiltration to the dry CF network (infiltration mechanism). In order to validate the compression mechanism, we developed an analytical model for predicting the void content of the PP/CF wet‐laid nonwoven composites. Good agreement between the predicted and the experimental void content suggests that void elimination follows the compression mechanism.
Highlights
An orthogonal experimental design reveals that the CF content and molding pressure can dominate the void content of the PP/CF wet‐laid nonwoven composite, while molding temperature and time have non‐significant effects.
A mechanism (i.e., compression mechanism) is proposed to explain the effect of CF content and molding conditions on the void content of the PP/CF wet‐laid nonwoven composite.
Good agreement between the experimental and the predicted void content validates the compression mechanism.
Accurate identifying and in‐depth understanding of the defect sites in a working nanomaterial could hinge on establishing specific defect‐activity relationships. Yet, atomically precise coinage‐metal ...nanoclusters (NCs) possessing surface vacancy defects are scarce primarily owing to challenges in the synthesis and isolation of such defective NCs. Herein we report a mixed‐ligand strategy to synthesizing an intrinsically chiral and metal‐deficient copper hydride‐rich NC Cu57H20(PET)36(TPP)4+ (Cu57H20). Its total structure (including hydrides) and electronic structure are well established by combined experimental and computational results. Crystal structure reveals Cu57H20 features a cube‐like Cu8 kernel embedded in a corner‐missing metal‐ligand shell of Cu49(PET)36(TPP)4. Single Cu vacancy defect site occurs at one corner of the shell, evocative of mono‐lacunary polyoxometalates. Theoretical calculations demonstrate that the above‐mentioned point vacancy causes one surface hydride exposed as an interfacial capping μ3‐H−, which is accessible in chemical reaction, as proved by deuterated experiment. Moreover, Cu57H20 shows catalytic activity in the hydrogenation of nitroarene. The success of this work opens the way for the research on well‐defined chiral metal‐deficient Cu and other metal NCs, including exploring their application in asymmetrical catalysis.
A chiral metal‐deficient Cu57 hydride‐rich nanocluster was prepared by a mixed‐ligand strategy. Its total structure and electronic structure were established by combined experimental and DFT results. Its optical and catalytic hydrogenation properties were studied.
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