{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:19:20Z","timestamp":1782937160192,"version":"3.54.5"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"publisher","award":["2022A1515010535"],"award-info":[{"award-number":["2022A1515010535"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Temporal lobe epilepsy (TLE) is a common and intractable form of epilepsy. There is a strong need to better understand molecular events underlying TLE and to find novel therapeutic agents. Here we aimed to investigate the role of Clock and ferroptosis in regulating TLE.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>TLE model was established by treating mice with kainic acid (KA). Regulatory effects of the Clock gene on KA-induced seizures and ferroptosis were evaluated using Clock knockout (Clock\u2212\/\u2212) mice. mRNA and protein levels were determined by quantitative real-time PCR and western blotting, respectively. Ferroptosis was assessed by measuring the levels of iron, GSH and ROS. Transcriptional regulation was studied using a combination of luciferase reporter, mobility shift and chromatin immunoprecipitation (ChIP) assays.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key findings<\/jats:title>\n                  <jats:p>We found that Clock ablation exacerbated KA-induced seizures in mice, accompanied by enhanced ferroptosis in the hippocampus. Clock ablation reduced the hippocampal expression of GPX4 and PPAR-\u03b3, two ferroptosis-inhibitory factors, in mice and in N2a cells. Moreover, Clock regulates diurnal expression of GPX4 and PPAR-\u03b3 in mouse hippocampus and rhythmicity in KA-induced seizures. Consistent with this finding, Clock overexpression up-regulated GPX4 and PPAR-\u03b3 and protected against ferroptosis in N2a cells. In addition, luciferase reporter, mobility shift and ChIP assays showed that CLOCK trans-activated Gpx4 and Ppar-\u03b3 through direct binding to the E-box elements in the gene promoters.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>CLOCK protects against KA-induced seizures through increased expression of GPX4 and PPAR-\u03b3 and inhibition of ferroptosis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jpp\/rgac042","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T15:15:02Z","timestamp":1655306102000},"page":"1640-1650","source":"Crossref","is-referenced-by-count":21,"title":["The <i>Clock<\/i> gene regulates kainic acid-induced seizures through inhibiting ferroptosis in mice"],"prefix":"10.1093","volume":"74","author":[{"given":"Fei","family":"Wang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Jinan University , Guangzhou ,","place":["China"]},{"name":"Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianxia","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jinan University , Guangzhou ,","place":["China"]},{"name":"Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine, Yichun University , Yichun ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Medicine, Jinan University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4629-5142","authenticated-orcid":false,"given":"Baojian","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"2024110604193530400_CIT0001","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0140-6736(18)32596-0","article-title":"Epilepsy in 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