Exploring the mechanisms of lithium neurotoxicity based on network toxicology and molecular docking
Wei Wei, Szu‐Yuan Pu, Chengxin Yan, Hongzao Yang, Hongwei Chen
Abstract
The rapid growth of lithium (Li)-related industrial activities and the application of Li-containing products have become an emerging human health concern. Li has been employed to treat human mental disorders; however, excessive Li salt accumulation can lead to brain damage. The mechanism of toxicity of long-term exposure to Li in the brain warrants further investigation. This research study established a network toxicology strategy to evaluate the molecular mechanisms and putative toxicity of lithium chloride (LiCl). The analysis of online databases identified 80 intersection targets for LiCl-induced neurotoxicity. Further refinements via STRING and Cytoscape software highlight 10 core targets. Furthermore, phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), apoptosis pathways, and mitogen-activated protein kinase (MAPK) were enriched. Molecular docking validated the robust interaction of core targets with Li + . In vivo analyses of mice brains revealed substantial pathological alterations, neuronal degeneration, and nerve cell apoptosis. LiCl elevated the mRNA level of core genes. Further, the phosphorylation status of core proteins was primarily modulated by LiCl. Our investigation employs novel strategies for assessing the environmental pollutant toxicity and gives theoretical basis for elaborating the LiCl-induced neurotoxicity-related molecular mechanism. This may be employed to guide risk assessment of environmental Li exposure. Proposed mechanism of lithium neurotoxicity based on network toxicology and molecular docking. • Applied network toxicology and molecular docking to analyze the putative toxicity of LiCl on neurotoxicity. • Uncover core targets and key pathways for LiCl-induced neurotoxicity. • Promote network toxicology and molecular docking strategies to analysis the toxicity and molecular biological mechanisms of potential environmental pollutants. • Exposure to Li at environmentally relevant concentrations is a risk factor for brain damage.