Ferroptosis: machinery and regulation

Autophagy, Journal Year: 2020, Volume and Issue: 17(9), P. 2054 - 2081

Published: Aug. 19, 2020

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which controlled integrated oxidation and antioxidant systems. The iron-containing enzyme lipoxygenase the main promoter ferroptosis producing hydroperoxides, its function relies on activation ACSL4-dependent biosynthesis. In contrast, selenium-containing GPX4 currently recognized as a central repressor ferroptosis, activity depends glutathione produced from cystine-glutamate antiporter SLC7A11. Many metabolic (especially involving iron, lipids, amino acids) degradation pathways (macroautophagy/autophagy ubiquitin-proteasome system) orchestrate complex ferroptotic response through direct or indirect regulation iron accumulation peroxidation. Although detailed mechanism membrane injury during remains mystery, ESCRT III-mediated plasma repair can make cells resistant to ferroptosis. Here, we review recent rapid progress in understanding molecular mechanisms focus epigenetic, transcriptional, posttranslational this process.Abbreviations: 2ME: beta-mercaptoethanol; α-KG: α-ketoglutarate; ccRCC: clear renal carcinoma; EMT: epithelial-mesenchymal transition; FAO: fatty acid beta-oxidation; GSH: glutathione; MEFs: mouse embryonic fibroblasts; MUFAs: monounsaturated acids; NO: nitric oxide; NOX: NADPH oxidase; PPP: pentose phosphate pathway; PUFA: polyunsaturated acid; RCD: death; RNS: reactive nitrogen species; ROS: oxygen RTAs: radical-trapping antioxidants; UPS: system; UTR: untranslated region.

Language: Английский

---

The Metabolic Underpinnings of Ferroptosis

Cell Metabolism, Journal Year: 2020, Volume and Issue: 32(6), P. 920 - 937

Published: Nov. 20, 2020

Language: Английский

---

Organelle-specific regulation of ferroptosis

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(10), P. 2843 - 2856

Published: Aug. 31, 2021

Language: Английский

---

Ferroptosis in Cancer Progression: Role of Noncoding RNAs

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(5), P. 1829 - 1843

Published: Jan. 1, 2022

Ferroptosis is a novel form of programmed cell death, and it characterized by iron-dependent oxidative damage, lipid peroxidation reactive oxygen species accumulation. Notable studies have revealed that ferroptosis plays vital roles in tumor occurrence abundant cells can inhibit progression. Recently, some noncoding RNAs (ncRNAs), particularly microRNAs, long RNAs, circular been shown to be involved biological processes ferroptosis, thus affecting cancer growth. However, the definite regulatory mechanism this phenomenon still unclear. To clarify issue, increasing focused on ncRNAs initiation development role progression various cancers, such as lung, liver, breast cancers. In review, we systematically summarized relationship between ferroptosis-associated Moreover, additional evidence needed identify ferroptosis-related This review will help us understand may provide new ideas for exploring diagnostic therapeutic biomarkers future.

Language: Английский

---

Non-coding RNAs and ferroptosis: potential implications for cancer therapy

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(6), P. 1094 - 1106

Published: April 14, 2022

Abstract Ferroptosis is a recently defined form of regulated cell death, which biochemically and morphologically distinct from traditional forms programmed death such as apoptosis or necrosis. It driven by iron, reactive oxygen species, phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage breakdown membrane integrity. Numerous cellular signaling pathways molecules involved the regulation ferroptosis, including enzymes control redox status. Alterations ferroptosis-regulating network can contribute to development various diseases, cancer. Evidence suggests ferroptosis commonly suppressed cancer cells, allowing them survive progress. However, cells resistant common chemotherapeutic drugs seem be highly susceptible inducers, highlighting great potential pharmacologic modulation for treatment. Non-coding RNAs (ncRNAs) considered master regulators processes, particularly where they have been implicated all hallmarks Recent work also demonstrated their involvement molecular ferroptosis. Hence, ncRNA-based therapeutics represent an exciting alternative modulate therapy. This review summarizes ncRNAs highlights underlying mechanisms light therapeutic applications.

Language: Английский

---

A graphical journey through iron metabolism, microRNAs, and hypoxia in ferroptosis

Redox Biology, Journal Year: 2022, Volume and Issue: 54, P. 102365 - 102365

Published: June 10, 2022

Ferroptosis is an iron-dependent form of cell death, which triggered by disturbed membrane integrity due to overproduction lipid peroxides. Induction ferroptosis comprises several alterations, i.e. altered iron metabolism, response oxidative stress, or peroxide production. At the physiological level transcription, translation, and microRNAs add appearance and/or activity building blocks that negatively positively balance ferroptosis. contributes tissue damage in case of, e.g., brain heart injury but may be desirable overcome chemotherapy resistance. For a more complete picture, it crucial also consider cellular microenvironment, during inflammation tumor context dominated hypoxia. This graphical review visualizes basic mechanisms ferroptosis, categorizes general inducers inhibitors puts focus on microRNAs, homeostasis, hypoxia as regulatory components.

Language: Английский

---

Curcumin suppresses tumorigenesis by ferroptosis in breast cancer

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(1), P. e0261370 - e0261370

Published: Jan. 18, 2022

Breast cancer (BC) is one of the most common malignant tumors found in females. Previous studies have demonstrated that curcumin, which a type polyphenol compound extracted from Curcuma longa underground rhizome, able to inhibit survival cells. However, functional role and mechanism curcumin BC are still unclear. The Cell Counting Kit-8 assay was performed examine effects on cell viability lines MDA-MB-453 MCF-7. levels lipid reactive oxygen species (ROS), malondialdehyde (MDA) production, intracellular Fe 2+ were determined assess ferroptosis. Western blot analysis also carried out detect protein levels. Finally, antitumorigenic effect identified xenograft tumor model. In present study, results indicated could dose-dependently suppress both MCF-7 Further revealed facilitated solute carrier family 1 member 5 (SLC1A5)-mediated ferroptosis cells by enhancing ROS levels, peroxidation end-product MDA accumulation, vivo experiments significantly hamper growth. Collectively, exhibited activity promoting SLC1A5-mediated ferroptosis, suggests its use as potential therapeutic agent for treatment BC.

Language: Английский

---

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Medicinal Research Reviews, Journal Year: 2023, Volume and Issue: 43(3), P. 614 - 682

Published: Jan. 19, 2023

Abstract Ferroptosis is an iron‐dependent cell death program that characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions structural features of ferroptosis‐inducing compounds might therefore open door efficient pharmacological strategies against aggressive, metastatic, therapy‐resistant cancer. We here summarize mechanisms requirements small molecules target central players ferroptosis. Focus placed on (i) glutathione peroxidase (GPX) 4, only GPX isoenzyme detoxifies complex membrane‐bound hydroperoxides, (ii) cystine/glutamate antiporter system X c − for regeneration, (iii) redox‐protective transcription factor nuclear erythroid 2‐related (NRF2), (iv) GPX4 repression combination with induced heme degradation via oxygenase‐1. deduce common ferroptotic activity highlight challenges development. Moreover, we critically discuss potential natural products lead structures provide comprehensive overview structurally diverse biogenic bioinspired trigger iron oxidation, inhibition thioredoxin/thioredoxin reductase or less defined modes action.

Language: Английский

---

Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers

Translational Lung Cancer Research, Journal Year: 2020, Volume and Issue: 9(4), P. 1569 - 1584

Published: Aug. 1, 2020

Abstract: Ferroptosis is a novel form of non-apoptotic regulated cell death (RCD), with distinct characteristics and functions in physical conditions multiple diseases such as cancers. Unlike apoptosis autophagy, this new RCD an iron-dependent features lethal accumulation reactive oxygen species (ROS) over production lipid peroxidation. Excessive iron from aberrant metabolisms or the maladjustment two main redox systems thiols peroxidation role major causes ROS generation, redox-acrive ferrous (intracellular labile iron) crucial factor for Regulation ferrroptosis also involves different pathways mevalonate pathway, P53 pathway p62-Keap1-Nuclear (erythroid-derived 2)-like 2 (Nrf2) pathway. roles double-edged sword either suppressing promoting tumor progression release signaling molecules microenvironment. Emerging evidence suggests ferroptosis potential target cancer therapy inducers including small nanomaterials have been developed. The application relates to overcoming drug resistance preventing metastasis, may become promising strategy combined other anti-cancer therapies. Here, we summarize characters its underlying basis cancer, followed by possible applications therapies challenges maintained.

Language: Английский

---

Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma

Cancer Cell International, Journal Year: 2021, Volume and Issue: 21(1)

Published: Feb. 18, 2021

Abstract Background Ferroptosis is a recently recognized non-apoptotic cell death that distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated ferroptosis involved in biological process of various cancers. However, role esophageal adenocarcinoma (EAC) remains unclear. This study aims to explore ferroptosis-related genes (FRG) expression profiles their prognostic values EAC. Methods The FRG data clinical information were downloaded Cancer Genome Atlas (TCGA) database. Univariate multivariate cox regressions used identify FRG, predictive ROC model was established using independent risk factors. GO KEGG enrichment analyses performed investigate bioinformatics functions significantly different (SDG) ferroptosis. Additionally, correlations immune cells assessed through single-sample gene set analysis (ssGSEA) TIMER Finally, SDG verified EAC specimens normal mucosal tissues. Results Twenty-eight screened 78 9 Enrichment showed these mainly related iron-related pathways metabolisms Gene network TP53, G6PD, NFE2L2 PTGS2 hub biology Cox regression four (CARS1, GCLM, GLS2 EMC2) had for overall survival (OS) (all P < 0.05). curve better ability score (AUC = 0.744). Immune types levels high-risk group significant with those low-risk experimental results confirmed ALOX5, NOX1 upregulated MT1G downregulated tissues compared Conclusions We identified differently expressed may involve These predicting patients’ OS targeting be an alternative therapy. Further are necessary verify our study.

Language: Английский

---