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      Ferroptosis-related genes are considered as potential targets for CPAP treatment of obstructive sleep apnea

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          Abstract

          Obstructive sleep apnea (OSA) is a common syndrome characterized by upper airway dysfunction during sleep. Continuous positive airway pressure (CPAP) is the most frequently utilized non-surgical treatment for OSA. Ferroptosis play a crucial role in the physiological diseases caused by chronic intermittent hypoxia, but its involvement in the development of OSA and the exact mechanisms have incompletely elucidated. GSE75097 microarray dataset was used to identify differentially expressed genes between OSA patients and CPAP-treated OSA patients. Subsequently, Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, STRING database, and FerrDb database were conducted to analyze the biological functions of differentially expressed genes and screen ferroptosis-related genes. Finally, GSE135917 dataset employed for validation. There were 1,540 differentially expressed genes between OSA patients and CPAP-treated OSA patients. These differentially expressed genes were significantly enriched in the regulation of interleukin-1-mediated signaling pathway and ferroptosis-related signaling pathway. Subsequently, 13 ferroptosis-related genes (DRD5, TSC22D3, TFAP2A, STMN1, DDIT3, MYCN, ELAVL1, JUN, DUSP1, MIB1, PSAT1, LCE2C, and MIR27A) were identified from the interaction between differentially expressed genes and FerrDb database, which are regarded as the potential targets of CPAP-treated OSA. These ferroptosis-related genes were mainly involved in cell proliferation and apoptosis and MAPK signaling pathway. Furthermore, DRD5 and TFAP2A were downregulated in OSA patients, which showed good diagnostic properties for OSA, but these abnormal signatures are not reversed with short-term effective CPAP therapy. In summary, the identification of 13 ferroptosis-related genes as potential targets for the CPAP treatment of OSA provides valuable insights into the development of novel, reliable, and accurate therapeutic options.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Metascape provides a biologist-oriented resource for the analysis of systems-level datasets

            Yingyao Zhou, Bin Zhou, Lars Pache … (2019)
            A critical component in the interpretation of systems-level studies is the inference of enriched biological pathways and protein complexes contained within OMICs datasets. Successful analysis requires the integration of a broad set of current biological databases and the application of a robust analytical pipeline to produce readily interpretable results. Metascape is a web-based portal designed to provide a comprehensive gene list annotation and analysis resource for experimental biologists. In terms of design features, Metascape combines functional enrichment, interactome analysis, gene annotation, and membership search to leverage over 40 independent knowledgebases within one integrated portal. Additionally, it facilitates comparative analyses of datasets across multiple independent and orthogonal experiments. Metascape provides a significantly simplified user experience through a one-click Express Analysis interface to generate interpretable outputs. Taken together, Metascape is an effective and efficient tool for experimental biologists to comprehensively analyze and interpret OMICs-based studies in the big data era.
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              Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

              Suzy Torti, Donna D. Zhang, K.A. Woerpel … (2019)
              Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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                Author and article information

                Contributors
                Jing Huang: Role: Role:
                Hezi Zhang: URI : https://loop.frontiersin.org/people/1669753/overviewRole: Role:
                Lichao Cao: URI : https://loop.frontiersin.org/people/1648570/overviewRole: Role: Role:
                Fang Chen: Role: Role:
                Weinan Lin: Role: Role:
                Qinghua Lu: URI : https://loop.frontiersin.org/people/2039872/overviewRole: Role:
                Xiao Huang: Role: Role:
                Qi Weng: Role: Role:
                Qin Yang: URI : https://loop.frontiersin.org/people/2545199/overviewRole: Role: Role: Role:
                Journal
                Journal ID (nlm-ta): Front Neurol
                Journal ID (iso-abbrev): Front Neurol
                Journal ID (publisher-id): Front. Neurol.
                Title: Frontiers in Neurology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-2295
                Publication date (Electronic): 21 December 2023
                Publication date Collection: 2023
                Volume: 14
                Electronic Location Identifier: 1320954
                Affiliations
                [1] 1Shantou University Medical College , Shantou, Guangdong Province, China
                [2] 2Shenzhen Nucleus Gene Technology Co., Ltd. , Shenzhen, Guangdong Province, China
                [3] 3Department of Respiratory Diseases, Shenzhen Children's Hospital , Shenzhen, Guangdong Province, China
                [4] 4Shenzhen Pediatrics Institute of Shantou University Medical College , Shenzhen, Guangdong Province, China
                Author notes

                Edited by: Erdem Tüzün, Istanbul University, Türkiye

                Reviewed by: Vuslat Yilmaz, Istanbul University, Türkiye; Yunfei Xu, Central South University, China; Ilknur Sur Erdem, University of Oxford, United Kingdom

                *Correspondence: Qin Yang, yangqin0539@ 123456sina.com

                †These authors have contributed equally to this work

                Article
                DOI: 10.3389/fneur.2023.1320954
                PMC ID: 10764456
                PubMed ID: 38178888
                SO-VID: f102f9eb-809d-47cb-80f3-b721e0fc479d
                Copyright © Copyright © 2023 Huang, Zhang, Cao, Chen, Lin, Lu, Huang, Weng and Yang.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 13 October 2023
                Date accepted : 06 December 2023
                Page count
                Figures: 6, Tables: 3, Equations: 0, References: 47, Pages: 9, Words: 5692
                Funding
                Funded by: Shenzhen Children’s Hospital
                Award ID: LCYJ2022097
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Shenzhen Children’s Hospital clinical study (LCYJ2022097).
                Categories
                Subject: Neurology
                Subject: Original Research
                Custom metadata
                section-at-acceptance Neurological Biomarkers

                ScienceOpen disciplines: Neurology
                Keywords: obstructive sleep apnea,chronic intermittent hypoxia,continuous positive airway pressure,ferroptosis,bioinformatics analysis
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: obstructive sleep apnea, chronic intermittent hypoxia, continuous positive airway pressure, ferroptosis, bioinformatics analysis

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