{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T06:27:01Z","timestamp":1772000821761,"version":"3.50.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Ferroptosis, a newly defined iron-dependent programmed cell death, characterized by excessive accumulation of lipid peroxides and reactive oxygen species, is involved in epilepsy, particularly in those forms resistant to drugs. In a previous study, we have demonstrated that exposure of mouse cortical slices to the ferroptosis inducer RSL-3, induces interictal epileptiform discharges. To investigate the mechanisms underlying ferroptosis-induced epileptic activity in RSL-3-treated cortical slices, we analysed the expression of the main contributors to ferroptosis susceptibility in cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The expression of proteins involved in RSL-3 induced ferroptosis pathways were analysed on mouse cortical slices by Western blot and qRT-PCR. The epileptogenic response was investigated by electrophysiological patch clamp recordings, in current clamp mode, from layer 2\/3 mouse cortical slices.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In cortical neurons, the ferroptosis induction by RSL-3 was associated with a reduced expression of the GPX4\/GSH redox pathway, responsible for the clearance of lipid peroxides, and an upregulation of 15-LOX, which promotes the formation of lipid peroxides. Furthermore, the cysteine\/glutamate antiporter Xc\n                      <jats:sup>\u2212<\/jats:sup>\n                      , a modulator of excitotoxicity in the brain, was up-regulated either after RSL-3-treatment or by incubating neurons with 4-HNE, the bioactive product of lipid peroxidation. Interestingly, 4-HNE was able to generate spontaneous interictal bursts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our findings establish a direct link between lipid peroxidation and Xc\n                      <jats:sup>\u2212<\/jats:sup>\n                      activity. These results suggest that the xCT antiporter may represent a promising therapeutic target for treating ferroptosis-mediated drug-resistant epilepsy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncel.2026.1758230","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T05:33:27Z","timestamp":1771997607000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular mechanisms underlying the ferroptosis-induced epileptiform activity in mouse cortical slices"],"prefix":"10.3389","volume":"20","author":[{"given":"Sara","family":"Petrillo","sequence":"first","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Loia","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Giustizieri","sequence":"additional","affiliation":[{"name":"European Brain Research Institute (EBRI)-Rita Levi-Montalcini Foundation","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Torda","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Cairoli","sequence":"additional","affiliation":[{"name":"Research Unit of Metabolic Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca","family":"Goffredo","sequence":"additional","affiliation":[{"name":"Research Unit of Metabolic Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Trivisano","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Epilepsy and Movement Disorders, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"de Palma","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Epilepsy and Movement Disorders, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Vigevano","sequence":"additional","affiliation":[{"name":"Department of Developmental Disabilities, IRCCS San Raffaele","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Specchio","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Epilepsy and Movement Disorders, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE","place":["Rome, Italy"]},{"name":"University Hospitals KU","place":["Leuven, Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Cherubini","sequence":"additional","affiliation":[{"name":"European Brain Research Institute (EBRI)-Rita Levi-Montalcini Foundation","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiorella","family":"Piemonte","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS","place":["Rome, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3390\/biomedicines13020265","article-title":"Targeting Ferroptosis in rare neurological disorders including pediatric conditions: innovations and therapeutic challenges","volume":"13","author":"Alatawi","year":"2025","journal-title":"Biomedicine"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/(sici)1098-1136(199802)22:2<149:aid-glia6>3.0.co;2-2","article-title":"4-hydroxynonenal, a lipid peroxidation product, impairs glutamate transport in cortical astrocytes","volume":"22","author":"Blanc","year":"1998","journal-title":"Glia"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1042\/BST0330423","article-title":"Polyunsaturated fatty acids and inflammation","volume":"33","author":"Calder","year":"2005","journal-title":"Biochem. 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