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Developing disease\u2010modifying therapies (DMTs) has become important in epilepsy studies. Notably, focusing on iron metabolism and ferroptosis might be a strategy of DMTs for epilepsy. Blocking the acid\u2010sensing ion channel 1a (ASIC1a) has been reported to protect the brain from ischemic injury by reducing the toxicity of [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      . However, whether inhibiting ASIC1a could exert neuroprotective effects and become a novel target for DMTs, such as rescuing the ferroptosis following epilepsy, remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In our study, we explored the changes in ferroptosis\u2010related indices, including glutathione peroxidase (GPx) enzyme activity and levels of glutathione (GSH), iron accumulation, lipid degradation products\u2010malonaldehyde (MDA) and 4\u2010hydroxynonenal (4\u2010HNE) by collecting peripheral blood samples from adult patients with epilepsy. Meanwhile, we observed alterations in ASIC1a protein expression and mitochondrial microstructure in the epileptogenic foci of patients with drug\u2010resistant epilepsy. Next, we accessed the expression and function changes of ASIC1a and measured the ferroptosis\u2010related indices in the in\u00a0vitro 0\u2010Mg\n                      <jats:sup>2+<\/jats:sup>\n                      model of epilepsy with primary cultured neurons. Subsequently, we examined whether blocking ASIC1a could play a neuroprotective role by inhibiting ferroptosis in epileptic neurons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our study first reported significant changes in ferroptosis\u2010related indices, including reduced GPx enzyme activity, decreased levels of GSH, iron accumulation, elevated MDA and 4\u2010HNE, and representative mitochondrial crinkling in adult patients with epilepsy, especially in epileptogenic foci. Furthermore, we found that inhibiting ASIC1a could produce an inhibitory effect similar to ferroptosis inhibitor Fer\u20101, alleviate oxidative stress response, and decrease [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      overload by inhibiting the overexpressed ASIC1a in the in\u00a0vitro epilepsy model induced by 0\u2010Mg\n                      <jats:sup>2+<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Inhibiting ASIC1a has potent neuroprotective effects via alleviating [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      overload and regulating ferroptosis on the models of epilepsy and may act as a promising intervention in DMTs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.14596","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T05:51:22Z","timestamp":1707976282000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Inhibiting acid\u2010sensing ion channel exerts neuroprotective effects in experimental epilepsy via suppressing ferroptosis"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5403-6097","authenticated-orcid":false,"given":"Xiaorui","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital Capital Medical University  Beijing China"},{"name":"China National Clinical Research Center for Neurological Diseases  Beijing 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