Realgar‐Induced CNS Toxicity: Exploring OTC‐Mediated Ornithine Regulation of ZBTB7A Inhibits Astrocyte Glycolysis Based on the Liver–Brain Axis

Abstract Realgar, an arsenic‐containing 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‐induced central nervous system (CNS) toxicity has garnered significant attention. To elucidate the molecular mechanism underlying realgar‐induced CNS toxicity, conditional intervention animal models ( Zbtb7a GfABC1D KD/ Otc TBG OE/chrysophanol intervention) are established and exposed to realgar, and a C8‐D1A astrocyte cell line transfected with si‐ Zbtb7a is established and exposed to both iAs 3+ and ornithine. Single‐cell 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–brain barrier and accumulates in the frontal lobe. Within astrocytes, arsenic triggers ZBTB7A‐mediated transcriptional repression of the glycolytic genes Aldoa , Ldha , and Pgam1 , 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‐like 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‐induced neurological injuries, as well as new experimental bases and theoretical guidance for the use of rhubarb and realgar in traditional Chinese medicine.