As a type of lytic cell death driven by unrestricted lipid peroxidation and subsequent plasma membrane damage, ferroptosis occurs and develops because of sophisticated signals and regulatory ...mechanisms. The reactive oxygen species (ROS) used to initiate ferroptosis come from a variety of sources, including iron‐mediated Fenton reactions, mitochondrial ROS, and membrane‐associated ROS driven by the NOX protein family. Polyunsaturated fatty acid‐containing phospholipids are the main substrates of lipid peroxidation in ferroptosis, which is positively regulated by enzymes, such as ACSL4, LPCAT3, ALOXs, or POR. Selective activation of autophagic degradation pathways promotes ferroptosis by increasing iron accumulation to cause lipid peroxidation. In contrast, system xc–‐glutathione–GPX4 axis plays a central role in limiting lipid peroxidation, although other antioxidants (such as coenzyme Q10 and tetrahydrobiopterin) can also inhibit ferroptosis. A main nuclear mechanism of cell defense against ferroptosis is the activation of the NFE2L2‐dependent antioxidant response by transcriptionally upregulating the expression of antioxidants or cytoprotective genes. Additionally, the membrane damage caused by ferroptotic stimulus can be repaired by ESCRT‐III‐dependent membrane scission machinery. In this review, we summarize recent progress in understanding the signaling pathways and defense mechanisms of ferroptosis.
Ferroptosis is a type of oxidative stress‐mediated cell death characterized by iron accumulation, lipid peroxidation, and plasma membrane damage. Excessive autophagy can promote ferroptosis, whereas ESCRT‐III‐mediated membrane repair can limit ferroptosis. In this review, we highlight the current understanding of the main signaling pathways and defense mechanisms of ferroptosis.
To satisfy the increasing energy demands of portable electronics, electric vehicles, and miniaturized energy storage devices, improvements to lithium‐ion batteries (LIBs) are required to provide ...higher energy/power densities and longer cycle lives. Group IVA element (Si, Ge, Sn)‐based alloying/dealloying anodes are promising candidates for use as electrodes in next‐generation LIBs owing to their extremely high gravimetric and volumetric capacities, low working voltages, and natural abundances. However, due to the violent volume changes that occur during lithium‐ion insertion/extraction and the formation of an unstable solid electrolyte interface, the use of Group IVA element‐based anodes in commercial LIBs is still a great challenge. Evaluating the electrochemical performance of an anode in a full‐cell configuration is a key step in investigating the possible application of the active material in LIBs. In this regard, the recent progress and important approaches to overcoming and alleviating the drawbacks of Group IVA element‐based anode materials are reviewed, such as the severe volume variations during cycling and the relatively brittle electrode/electrolyte interface in full‐cell LIBs. Finally, perspectives and future challenges in achieving the practical application of Group IVA element‐based anodes in high‐energy and high‐power‐density LIB systems are proposed.
Group IVA element (Si, Ge, Sn)‐based alloying/dealloying electrodes are promising candidates for anodes in next‐generation lithium–ion batteries owing to their high gravimetric and volumetric capacities, low working voltages, and natural abundance. The recent progress and important approaches in overcoming and alleviating the drawbacks of Group IVA element‐based anodes in full‐cell configurations are reviewed.
Damage-associated molecular pattern molecules (DAMPs) are endogenous danger signals that alert the innate immune system and shape the inflammation response to cell death. However, the release and ...activity of DAMPs in ferroptosis, a recently identified form of regulated necrosis characterized by iron overload and lipid peroxidation, still remain poorly understood. Here, we demonstrate that HMGB1 is a DAMP released by ferroptotic cells in an autophagy-dependent manner. Both type I and II ferroptosis activators, including erastin, sorafenib, RSL3, and FIN56, induce HMGB1 release in cancer and noncancer cells. In contrast, genetic ablation (using ATG5−/− or ATG7−/− cells) or pharmacologic inhibition (the administration of bafilomycin A1 or chloroquine) of autophagy was found to block ferroptosis activator-induced HMGB1 release. Mechanically, autophagy-mediated HDAC inhibition promotes HMGB1 acetylation, resulting in HMGB1 release in ferroptosis. Moreover, AGER, but not TLR4, is required for HMGB1-mediated inflammation in macrophages in response to ferroptotic cells. These studies suggest that HMGB1 inhibition might have some potential therapeutic effects in ferroptosis-associated human disease.
•Ferroptosis activators induce HMGB1 release.•Autophagy promotes HMGB1 release in ferroptosis.•Autophagy promotes HMGB1 acetylation in ferroptosis.•HMGB1-AGER pathway mediates inflammation response in ferroptosis.
Aromatic metalla‐annulenes are important aromatic compounds, research into which has been mainly concentrated on metal‐benzenes and their lower homologues. Reports on their superior homologs are ...rare, and this has greatly limited the systematic study of their properties. In this work, a series of osma‐dehydro11annulenes with good air and thermal stability were prepared in high yields through a simple 10+1 strategy, by incorporating a metal fragment into conjugated ten‐carbon chains in a one‐pot reaction. They are the first monometallic aromatic metalla‐nannulenes with the ring size larger than 6, and their Craig‐Hückel hybrid aromaticity is supported by various physical and computational parameters. Besides, these complexes show versatile reactivities, not only giving further evidence for their aromaticity, but also demonstrating their physical and chemical properties can easily be regulated. This work enriches the metalla‐aromatic chemistry, and provides a new avenue for the synthesis of large metalla‐annulenes with different ring sizes.
A series of metalla‐dehydro11annulenes with Craig‐Hückel hybrid aromaticity, were constructed by a one pot 10+1 strategy. They are the first monometallic aromatic metalla‐nannulenes with the ring size larger than 6, and their special aromaticity was confirmed both experimentally and theoretically. This work provides a method to construct large metalla‐annulenes with different ring sizes, which is significant for metalla‐aromatic chemistry.
Many new types of regulated cell death have been recently implicated in human health and disease. These regulated cell deaths have different morphological, genetic, biochemical, and functional ...hallmarks. Ferroptosis was originally described as a carcinogenic RAS-dependent non-apoptotic cell death, and is now defined as a type of regulated necrosis characterized by iron accumulation, lipid peroxidation, and the release of damage-associated molecular patterns (DAMPs). Multiple oxidative and antioxidant systems, acting together autophagy machinery, shape the process of lipid peroxidation during ferroptosis. In particular, the production of reactive oxygen species (ROS) that depends on the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and the mitochondrial respiratory chain promotes lipid peroxidation by lipoxygenase (ALOX) or cytochrome P450 reductase (POR). In contrast, the glutathione (GSH), coenzyme Q10 (CoQ10), and tetrahydrobiopterin (BH
4
) system limits oxidative damage during ferroptosis. These antioxidant processes are further transcriptionally regulated by nuclear factor, erythroid 2-like 2 (NFE2L2/NRF2), whereas membrane repair during ferroptotic damage requires the activation of endosomal sorting complexes required for transport (ESCRT)-III. A further understanding of the process and function of ferroptosis may provide precise treatment strategies for disease.
Although it has long been deemed "undruggable", with the development of drugs specifically binding the KRAS-G12C mutant protein, clinical trials that directly inhibit oncogenic RAS have recently made ...promising improvements. In particular, the covalent KRAS-G12C inhibitors sotorasib and adagrasib are used to treat patients with advanced non-small cell lung cancer (NSCLC) carrying KRAS-G12C mutations. Unfortunately, the vast majority of patients do not respond to KRAS-G12C inhibitor therapy, mainly due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improving the understanding of drug response in the tumor microenvironment may continue to promote the design, testing, and clinical application of KRAS-G12C inhibitors.
Cervical cancer remains a serious health problem till now, with nearly 500,000 women cases diagnosed each year around the world. Long noncoding RNA (lncRNA) is a novel class of RNA transcripts (>200 ...nucleotides in length) participating in gene transcription, cell proliferation, differentiation, and drug resistance. This study aimed to explore the regulatory relationship among lncRNA NCK1‐AS1, miR‐134‐5p, and MutS protein homolog 2 (MSH2), so that the resistance against cisplatin in cervical cancer treatment could be better understood. Comprehensive lncRNA profiling analysis was performed to screen lncRNAs differentially expressed in cervical cancer. The expression patterns of miR‐134‐5p, NCK1‐AS1, and MSH2 were evaluated in cancerous tissues and adjacent normal tissues obtained from 75 cervical cancer patients. Subsequently, anti‐NCK1‐AS1 small interfering RNA, miR‐134‐5p mimics, and miR‐134‐5p inhibitors were transfected into cervical cancer cells, and the effects of these transcripts on cisplatin resistance and cell apoptosis were investigated. The regulatory relationship among NCK1‐AS1, miR‐134‐5p, and MSH2 was identified using a dual‐luciferase reporter gene assay, and the results were further validated by RNA pull‐down and RNA immunoprecipitation assays. Based on the microarray data of GSE63514 and GSE27678, NCK1‐AS1 was upregulated in cervical cancer. Increased expression of NCK1‐AS1, MSH2, and decreased expression of miR‐134‐5p were observed in cervical cancer tissues. In addition, NCK1‐AS1 competitively bound to miR‐134‐5p to regulate MSH2. Therefore, si‐NCK1‐AS1 and miR‐134‐5p mimic both reduced MSH2 activity and increased cisplatin‐induced apoptosis in cervical cancer cells. Taken together, NCK1‐AS1 may become a novel target in improving the chemotherapeutic response and survival of cervical cancer patients.
This study aimed to explore the regulatory relationship among long noncoding RNA NCK1‐AS1, miR‐134‐5p, and MutS protein homolog 2, so that the resistance against cisplatin in cervical cancer treatment could be better understood. NCK1‐AS1 may become a novel target in improving the chemotherapeutic response and survival of cervical cancer patients.
Macroautophagy (hereafter referred to as autophagy) involves an intracellular degradation and recycling system that, in a context-dependent manner, can either promote cell survival or accelerate ...cellular demise. Ferroptosis was originally defined in 2012 as an iron-dependent form of cancer cell death different from apoptosis, necrosis, and autophagy. However, this latter assumption came into question because, in response to ferroptosis activators (e.g., erastin and RSL3), autophagosomes accumulate, and because components of the autophagy machinery (e.g., ATG3, ATG5, ATG4B, ATG7, ATG13, and BECN1) contribute to ferroptotic cell death. In particular, NCOA4-facilitated ferritinophagy, RAB7A-dependent lipophagy, BECN1-mediated system xc− inhibition, STAT3-induced lysosomal membrane permeabilization, and HSP90-associated chaperone-mediated autophagy can promote ferroptosis. In this review, we summarize current knowledge on the signaling pathways involved in ferroptosis, while focusing on the regulation of autophagy-dependent ferroptotic cell death. The molecular comprehension of these phenomena may lead to the development of novel anticancer therapies.
Ferroptosis has become a topic of rapidly growing interest in recent years, and has possible therapy implications in cancer therapy. Although excessive autophagy may contribute to ferroptosis, its ...underlying molecular mechanism remains largely unknown. Here, we provide novel evidence that the interplay between the signals of mechanistic target of rapamycin kinase (MTOR) and glutathione peroxidase 4 (GPX4) modulates autophagy-dependent ferroptosis in human pancreatic cancer cells. Both the classical autophagy inducer rapamycin and the classical ferroptosis activator RSL3 can block MTOR activation and cause GPX4 protein degradation in human pancreatic cancer cells. Moreover, GPX4 plays an essential role in the inhibition of autophagy-dependent ferroptosis induced by rapamycin and RSL3. Consequently, GPX4 depletion by RNAi enhances the anticancer activity of rapamycin and RSL3 in vitro or in vivo. These findings not only increase our understanding of stress responses in cell death, but may also raise the possibility of developing new antitumor therapy targeting autophagy-dependent cell death.
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Experimental evidence has shown that per- and polyfluoroalkyl substances (PFAS) alternatives and mixtures may exert hepatotoxic effects in animals. However, epidemiological evidence ...is limited. This research aimed to explore associations of PFAS and the alternatives with liver function in a general adult population. The study participants consisted of 1,303 adults from a community-based cross-sectional investigation in Guangzhou, China, from November 2018 to August 2019. We selected 13 PFAS with detection rates > 85% in serum samples and focused on perfluorooctane-sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and their alternatives 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), 8:2 Cl-PFESA, and perfluorohexanoic acid (PFHxA) as predictors of outcome. Six liver function biomarkers (ALB, ALT, AST, GGT, ALP, and DBIL) were chosen as outcomes. We applied regression models with restricted cubic spline function to explore correlations between single PFAS and liver function and inspected the combined effect of PFAS mixtures on liver by applying Bayesian kernel machine regression (BKMR). We discovered positive associations among PFAS and liver function biomarkers except for ALP. For example, compared with the 25th percentile of PFAS concentration, the level of ALT increased by 12.36% (95% CI: 7.91%, 16.98%) for ln-6:2 Cl-PFESA, 5.59% (95% CI: 2.35%, 8.92%) for ln-8:2 Cl-PFESA, 3.56% (95% CI: −0.39%, 7.68%) for ln-PFHxA, 13.91% (95% CI: 8.93%, 19.13%) for ln-PFOA, and 14.25% (95% CI: 9.91%, 18.77%) for ln-PFOS at their 75th percentile. In addition, higher exposed serum PFAS was found to be correlated with greater odds of abnormal liver function. Analysis from BKMR models also showed an adverse association between PFAS mixtures and liver function. The combined effect of the PFAS mixture appeared to be non-interactive, in which PFOS was the main contributor to the overall effect. Our findings provide evidence of associations between PFAS alternatives, PFAS mixtures, and liver function in the general adult population.
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