{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:13:51Z","timestamp":1787019231375,"version":"build-2736575974"},"reference-count":28,"publisher":"SAGE Publications","issue":"4-6","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants & Redox Signaling"],"published-print":{"date-parts":[[2026,2]]},"abstract":"\n Aims:<\/jats:title>\n \n Hypothyroidism frequently causes myocardial injury, but the role of\n thyroid hormone receptor alpha<\/jats:italic>\n (\n THRA<\/jats:italic>\n ) remains unclear. This study investigated the function and mechanism of\n THRA<\/jats:italic>\n in hypothyroidism-associated cardiac damage.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n A propylthiouracil (PTU)-induced hypothyroid mouse model was utilized, incorporating wild-type and\n THRA<\/jats:italic>\n -knockout (KO) groups with or without thyroxine (T4) treatment. Systemic parameters, cardiac injury, histopathology, and molecular pathways were analyzed using enzyme-linked immunosorbent assay, immunohistochemistry, Western blot, quantitative polymerase chain reaction, RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n PTU-induced hypothyroidism significantly reduced body weight, impaired cardiac function, and dysregulated thyroid hormones.\n THRA<\/jats:italic>\n KO exacerbated these effects and completely abolished the therapeutic response to T4. Crucially, group KO-M markedly elevated markers of ferroptosis, including iron overload, malondialdehyde, and reactive oxygen species, while suppressing the reduced-to-oxidized glutathione ratio (GSH\/GSSG) and key antiferroptotic proteins like\n glutathione peroxidase 4<\/jats:italic>\n (\n GPX4<\/jats:italic>\n ), compared with group M. Mechanistically, we identified\n GATA binding protein 4<\/jats:italic>\n (\n GATA4<\/jats:italic>\n ) as an upstream transcriptional activator of\n THRA<\/jats:italic>\n . Furthermore,\n THRA<\/jats:italic>\n itself directly bound to the\n GPX4<\/jats:italic>\n promoter and transactivated its expression. This\n GATA4<\/jats:italic>\n -\n THRA<\/jats:italic>\n -\n GPX4<\/jats:italic>\n axis was essential for cardioprotection, alongside modulation of the\n phosphoinositide 3-kinase<\/jats:italic>\n \/\n protein kinase B<\/jats:italic>\n signaling pathway.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n \n This study defines the\n GATA4<\/jats:italic>\n -\n THRA<\/jats:italic>\n -\n GPX4<\/jats:italic>\n transcriptional axis as a crucial mechanism that protects the heart from hypothyroidism-driven ferroptosis, uncovering a previously unrecognized transcriptional axis that is crucial for cardioprotection during hypothyroidism.\n Antioxid. Redox Signal.<\/jats:italic>\n 44, 236\u2013250.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1177\/15230864251399166","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T05:13:14Z","timestamp":1764220394000},"page":"236-250","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["THRA Orchestrates Myocardial Protection Against Hypothyroidism-Induced Ferroptosis\n via<\/i>\n the GATA4-GPX4 Transcriptional Cascade"],"prefix":"10.1177","volume":"44","author":[{"given":"Zhang","family":"Runfang","sequence":"first","affiliation":[{"name":"The Second Clinical College of Zhengzhou University, Zhengzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianen","family":"Fa","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"e_1_3_5_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19010088"},{"key":"e_1_3_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2020.03.016"},{"key":"e_1_3_5_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfr080"},{"key":"e_1_3_5_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00735-4"},{"key":"e_1_3_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-023-02815-2"},{"key":"e_1_3_5_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.2.368"},{"key":"e_1_3_5_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043393"},{"key":"e_1_3_5_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0825"},{"key":"e_1_3_5_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10050667"},{"key":"e_1_3_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101328"},{"key":"e_1_3_5_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq361"},{"key":"e_1_3_5_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21228765"},{"key":"e_1_3_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2021.106094"},{"key":"e_1_3_5_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.636"},{"key":"e_1_3_5_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241813845"},{"key":"e_1_3_5_17_1","doi-asserted-by":"publisher","DOI":"10.1586\/14779072.2014.957674"},{"key":"e_1_3_5_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102936"},{"key":"e_1_3_5_19_1","doi-asserted-by":"publisher","DOI":"10.14797\/mdcj-13-2-55"},{"key":"e_1_3_5_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-023-01902-9"},{"key":"e_1_3_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.102035"},{"key":"e_1_3_5_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1241282"},{"key":"e_1_3_5_23_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867329666220630144648"},{"key":"e_1_3_5_24_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/6653202"},{"key":"e_1_3_5_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.789948"},{"key":"e_1_3_5_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22970-x"},{"key":"e_1_3_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e24562"},{"key":"e_1_3_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115765"},{"key":"e_1_3_5_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000315077"}],"container-title":["Antioxidants & Redox Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/15230864251399166","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/15230864251399166","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/15230864251399166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:56:20Z","timestamp":1777377380000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/15230864251399166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":28,"journal-issue":{"issue":"4-6","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1177\/15230864251399166"],"URL":"https:\/\/doi.org\/10.1177\/15230864251399166","relation":{},"ISSN":["1523-0864","1557-7716"],"issn-type":[{"value":"1523-0864","type":"print"},{"value":"1557-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}