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Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury
Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed...
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| Published in: | Neurochemical research 2024-07, Vol.49 (7), p.1806-1822 |
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| creator | Zhao, Lan Li, Yanan Wang, Wei Qi, Xue Wang, Su Song, Wenqin Li, Ting Gao, Wenwei |
| description | Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (
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| doi_str_mv | 10.1007/s11064-024-04146-4 |
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| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3051939161</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3062956362</sourcerecordid><originalsourceid>FETCH-LOGICAL-c375t-72e3ce59c3190ded55212f97aec7ad01c0f280acea993d14644a1a7521bbcf533</originalsourceid><addsrcrecordid>eNp9kTtPwzAUhS0EouXxBxhQJBaWgF-J8YgqHpUKlaoyW65z07pKnGAnSP33uLSAxMBgeTjfOb7XB6ELgm8IxuI2EIJznmIaDyc8T_kBGpJMsDSXmB2iIWZRZkTiAToJYY1xtFFyjAbsThDGmRiiegbLvtKddcvkdTS95-kLFFZ3UCSP4L2NQtOu9HKTlI1P5ivwuoW-syYZuw78B7jONi6xLhmBh4XXVTIOZgW11ekMWvBlH7bA2K17vzlDR6WuApzv71P09vgwHz2nk-nTeHQ_SQ0TWZcKCsxAJs129gKKLKOEllJoMEIXmBhc0jusDWgpWRE351wTLSK1WJgyY-wUXe9yW9-89xA6VdtgoKq0g6YPiuGMSCZJTiJ69QddN713cbpI5VRmOctppOiOMr4JwUOpWm9r7TeKYLUtQ-3KULEM9VWG4tF0uY_uFzUUP5bv348A2wEhSm4J_vftf2I_AXBxlS8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3062956362</pqid></control><display><type>article</type><title>Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury</title><source>Springer Nature</source><creator>Zhao, Lan ; Li, Yanan ; Wang, Wei ; Qi, Xue ; Wang, Su ; Song, Wenqin ; Li, Ting ; Gao, Wenwei</creator><creatorcontrib>Zhao, Lan ; Li, Yanan ; Wang, Wei ; Qi, Xue ; Wang, Su ; Song, Wenqin ; Li, Ting ; Gao, Wenwei</creatorcontrib><description><![CDATA[Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (
P
< 0.05). This activation contributed to oxidative stress (
P
< 0.05), enhanced autophagy (
P
< 0.05) and cell death (
P
< 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (
P
< 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (
P
< 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (
P
< 0.05), oxidative stress (
P
< 0.05), and cell damage (
P
< 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (
P
< 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (
P
< 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (
P
< 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.]]></description><identifier>ISSN: 0364-3190</identifier><identifier>ISSN: 1573-6903</identifier><identifier>EISSN: 1573-6903</identifier><identifier>DOI: 10.1007/s11064-024-04146-4</identifier><identifier>PMID: 38713437</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; Autophagy ; Autophagy - drug effects ; Autophagy - physiology ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Brain Ischemia - drug therapy ; Brain Ischemia - metabolism ; Cell Biology ; Cell death ; Cell Line ; Chelating agents ; Damage ; Deferoxamine ; Ferritins - metabolism ; Ferrous ions ; Global health ; Glucose ; Hypoxia ; Injuries ; Iron ; Ischemia ; Mice ; Molecular modelling ; Neurochemistry ; Neurology ; Neurosciences ; Nuclear Receptor Coactivators - metabolism ; Original Paper ; Oxidative stress ; Oxidative Stress - drug effects ; Oxidative Stress - physiology ; Oxygen ; Public health ; Reperfusion ; Reperfusion Injury - drug therapy ; Reperfusion Injury - metabolism ; Stimulators</subject><ispartof>Neurochemical research, 2024-07, Vol.49 (7), p.1806-1822</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-72e3ce59c3190ded55212f97aec7ad01c0f280acea993d14644a1a7521bbcf533</citedby><cites>FETCH-LOGICAL-c375t-72e3ce59c3190ded55212f97aec7ad01c0f280acea993d14644a1a7521bbcf533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38713437$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Lan</creatorcontrib><creatorcontrib>Li, Yanan</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Qi, Xue</creatorcontrib><creatorcontrib>Wang, Su</creatorcontrib><creatorcontrib>Song, Wenqin</creatorcontrib><creatorcontrib>Li, Ting</creatorcontrib><creatorcontrib>Gao, Wenwei</creatorcontrib><title>Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury</title><title>Neurochemical research</title><addtitle>Neurochem Res</addtitle><addtitle>Neurochem Res</addtitle><description><![CDATA[Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (
P
< 0.05). This activation contributed to oxidative stress (
P
< 0.05), enhanced autophagy (
P
< 0.05) and cell death (
P
< 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (
P
< 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (
P
< 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (
P
< 0.05), oxidative stress (
P
< 0.05), and cell damage (
P
< 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (
P
< 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (
P
< 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (
P
< 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.]]></description><subject>Animals</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Autophagy - physiology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain Ischemia - drug therapy</subject><subject>Brain Ischemia - metabolism</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell Line</subject><subject>Chelating agents</subject><subject>Damage</subject><subject>Deferoxamine</subject><subject>Ferritins - metabolism</subject><subject>Ferrous ions</subject><subject>Global health</subject><subject>Glucose</subject><subject>Hypoxia</subject><subject>Injuries</subject><subject>Iron</subject><subject>Ischemia</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>Neurochemistry</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Nuclear Receptor Coactivators - metabolism</subject><subject>Original Paper</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - physiology</subject><subject>Oxygen</subject><subject>Public health</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - drug therapy</subject><subject>Reperfusion Injury - metabolism</subject><subject>Stimulators</subject><issn>0364-3190</issn><issn>1573-6903</issn><issn>1573-6903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kTtPwzAUhS0EouXxBxhQJBaWgF-J8YgqHpUKlaoyW65z07pKnGAnSP33uLSAxMBgeTjfOb7XB6ELgm8IxuI2EIJznmIaDyc8T_kBGpJMsDSXmB2iIWZRZkTiAToJYY1xtFFyjAbsThDGmRiiegbLvtKddcvkdTS95-kLFFZ3UCSP4L2NQtOu9HKTlI1P5ivwuoW-syYZuw78B7jONi6xLhmBh4XXVTIOZgW11ekMWvBlH7bA2K17vzlDR6WuApzv71P09vgwHz2nk-nTeHQ_SQ0TWZcKCsxAJs129gKKLKOEllJoMEIXmBhc0jusDWgpWRE351wTLSK1WJgyY-wUXe9yW9-89xA6VdtgoKq0g6YPiuGMSCZJTiJ69QddN713cbpI5VRmOctppOiOMr4JwUOpWm9r7TeKYLUtQ-3KULEM9VWG4tF0uY_uFzUUP5bv348A2wEhSm4J_vftf2I_AXBxlS8</recordid><startdate>20240701</startdate><enddate>20240701</enddate><creator>Zhao, Lan</creator><creator>Li, Yanan</creator><creator>Wang, Wei</creator><creator>Qi, Xue</creator><creator>Wang, Su</creator><creator>Song, Wenqin</creator><creator>Li, Ting</creator><creator>Gao, Wenwei</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20240701</creationdate><title>Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury</title><author>Zhao, Lan ; Li, Yanan ; Wang, Wei ; Qi, Xue ; Wang, Su ; Song, Wenqin ; Li, Ting ; Gao, Wenwei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-72e3ce59c3190ded55212f97aec7ad01c0f280acea993d14644a1a7521bbcf533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Autophagy - physiology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain Ischemia - drug therapy</topic><topic>Brain Ischemia - metabolism</topic><topic>Cell Biology</topic><topic>Cell death</topic><topic>Cell Line</topic><topic>Chelating agents</topic><topic>Damage</topic><topic>Deferoxamine</topic><topic>Ferritins - metabolism</topic><topic>Ferrous ions</topic><topic>Global health</topic><topic>Glucose</topic><topic>Hypoxia</topic><topic>Injuries</topic><topic>Iron</topic><topic>Ischemia</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>Neurochemistry</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Nuclear Receptor Coactivators - metabolism</topic><topic>Original Paper</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - physiology</topic><topic>Oxygen</topic><topic>Public health</topic><topic>Reperfusion</topic><topic>Reperfusion Injury - drug therapy</topic><topic>Reperfusion Injury - metabolism</topic><topic>Stimulators</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Lan</creatorcontrib><creatorcontrib>Li, Yanan</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Qi, Xue</creatorcontrib><creatorcontrib>Wang, Su</creatorcontrib><creatorcontrib>Song, Wenqin</creatorcontrib><creatorcontrib>Li, Ting</creatorcontrib><creatorcontrib>Gao, Wenwei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Neurochemical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Lan</au><au>Li, Yanan</au><au>Wang, Wei</au><au>Qi, Xue</au><au>Wang, Su</au><au>Song, Wenqin</au><au>Li, Ting</au><au>Gao, Wenwei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury</atitle><jtitle>Neurochemical research</jtitle><stitle>Neurochem Res</stitle><addtitle>Neurochem Res</addtitle><date>2024-07-01</date><risdate>2024</risdate><volume>49</volume><issue>7</issue><spage>1806</spage><epage>1822</epage><pages>1806-1822</pages><issn>0364-3190</issn><issn>1573-6903</issn><eissn>1573-6903</eissn><abstract><![CDATA[Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (
P
< 0.05). This activation contributed to oxidative stress (
P
< 0.05), enhanced autophagy (
P
< 0.05) and cell death (
P
< 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (
P
< 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (
P
< 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (
P
< 0.05), oxidative stress (
P
< 0.05), and cell damage (
P
< 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (
P
< 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (
P
< 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (
P
< 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.]]></abstract><cop>New York</cop><pub>Springer US</pub><pmid>38713437</pmid><doi>10.1007/s11064-024-04146-4</doi><tpages>17</tpages></addata></record> |
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| subjects | Animals Autophagy Autophagy - drug effects Autophagy - physiology Biochemistry Biomedical and Life Sciences Biomedicine Brain Ischemia - drug therapy Brain Ischemia - metabolism Cell Biology Cell death Cell Line Chelating agents Damage Deferoxamine Ferritins - metabolism Ferrous ions Global health Glucose Hypoxia Injuries Iron Ischemia Mice Molecular modelling Neurochemistry Neurology Neurosciences Nuclear Receptor Coactivators - metabolism Original Paper Oxidative stress Oxidative Stress - drug effects Oxidative Stress - physiology Oxygen Public health Reperfusion Reperfusion Injury - drug therapy Reperfusion Injury - metabolism Stimulators |
| title | Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury |
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