{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:41:26Z","timestamp":1791916886210,"version":"4.3.4"},"reference-count":71,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Realgar, an arsenic\u2010containing traditional Chinese medicine, is commonly used in clinical practice. However, prolonged, excessive, or uncontrolled administration of Chinese patent medicines containing realgar can occasionally induce adverse effects. Notably, realgar\u2010induced central nervous system (CNS) toxicity has garnered significant attention. To elucidate the molecular mechanism underlying realgar\u2010induced CNS toxicity, conditional intervention animal models (\n                    <jats:italic>Zbtb7a<\/jats:italic>\n                    <jats:sup>GfABC1D<\/jats:sup>\n                    KD\/\n                    <jats:italic>Otc<\/jats:italic>\n                    <jats:sup>TBG<\/jats:sup>\n                    OE\/chrysophanol intervention) are established and exposed to realgar, and a C8\u2010D1A astrocyte cell line transfected with si\u2010\n                    <jats:italic>Zbtb7a<\/jats:italic>\n                    is established and exposed to both iAs\n                    <jats:sup>3+<\/jats:sup>\n                    and ornithine. Single\u2010cell transcriptome sequencing, metabolomic analysis, as well as neurobehavioral, molecular biological, and histopathological experiments are performed. These results demonstrate that arsenic derived from realgar crosses the blood\u2013brain barrier and accumulates in the frontal lobe. Within astrocytes, arsenic triggers ZBTB7A\u2010mediated transcriptional repression of the glycolytic genes\u00a0\n                    <jats:italic>Aldoa<\/jats:italic>\n                    ,\u00a0\n                    <jats:italic>Ldha<\/jats:italic>\n                    , and\u00a0\n                    <jats:italic>Pgam1<\/jats:italic>\n                    , consequently reducing lactic acid levels. This cascade of events culminates in energy deficits within the frontal lobe, promoting apoptosis and oxidative damage. These pathological changes manifest behaviorally as decreased learning and memory capacity, diminished spontaneous exploration, and the development of anxiety\u2010like behaviors. Furthermore, realgar inhibits hepatic ornithine transcarbamylase (OTC), disrupting the hepatic ornithine cycle. This disruption leads to ornithine accumulation, which in turn modulates the transcription factor ZBTB7A in astrocytes, indirectly exacerbating the neurotoxic effects of arsenic. In addition, chrysophanol antagonizes the toxic effects of realgar on the CNS and liver by protecting astrocyte glycolytic function and the hepatic ornithine cycle. This study provides new perspectives and targets for the prevention and treatment of realgar\u2010induced neurological injuries, as well as new experimental bases and theoretical guidance for the use of rhubarb and realgar in traditional Chinese medicine.\n                  <\/jats:p>","DOI":"10.1002\/advs.202502591","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T19:48:01Z","timestamp":1763754481000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Realgar\u2010Induced CNS Toxicity: Exploring OTC\u2010Mediated Ornithine Regulation of ZBTB7A Inhibits Astrocyte Glycolysis Based on the Liver\u2013Brain Axis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6827-3548","authenticated-orcid":false,"given":"Ping","family":"Ye","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyong","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingang","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health Mudanjiang Medical University  Mudanjiang Heilongjiang 157011 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengbo","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"},{"name":"The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic  Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Shimadzu (China) Co., LTD  Shenyang Branch Shenyang 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4427-9405","authenticated-orcid":false,"given":"Hong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention Ministry of Education China Medical University  Shenyang Liaoning 110122 China"},{"name":"School of Public Health China Medical University  Shenyang Liaoning 110122 China"},{"name":"The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic  Liaoning 110122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2017.08.037"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2018.03.012"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2011.03.071"},{"key":"e_1_2_9_4_1","first-page":"2010","volume":"31","author":"Zhang L.","year":"2006","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"e_1_2_9_5_1","first-page":"433","volume":"44","author":"Song L. 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