Abstract
Background/Objectives: Semen Ziziphi Spinosae (SZS), a medicinal and edible traditional Chinese herb, has been widely used to treat insomnia. As critical regulators of the central nervous system, astrocytes play a pivotal role in maintaining sleep homeostasis. However, the mechanisms by which SZS modulates astrocytic function to improve sleep remain unclear. Methods: In this study, we employed an integrated transcriptomics and metabolomics approach to investigate the protective effects of SZS extract against lipopolysaccharide (LPS)-induced inflammatory injury and metabolic dysfunction in astrocytes. Results: Transcriptomic analysis revealed that SZS ameliorates cellular damage (including apoptosis, autophagy, and cell cycle dysregulation) through a FOXO3-centric signaling network. Concurrently, SZS restored cellular energy metabolism by increasing ATP production and reducing Ca(2+) overload, thereby activating the AMPK signaling pathway to support normal astrocytic function. Metabolomic profiling further demonstrated that SZS-mediated restoration of energy homeostasis sustains ABC transporter activity, which in turn modulates neurotransmitter (serotonin, L-glutamic acid, adenosine), metabolic mediators (leukotrienes, palmitoylethanolamide, succinic acid), and nucleotide (uridine 5'-diphosphate). These coordinated changes normalized GABAergic synapse activity and neuroactive ligand receptor interactions, ultimately resolving neural metabolic network disturbances. Conclusions: Our findings elucidate a novel FOXO3-energy metabolism-ABC transporter axis through which SZS extract attenuates neuroinflammation and metabolic dysfunction in astrocytes and exerts sleep-promoting and neuroprotective effects. This study provides a scientific foundation for understanding the modern pharmacological mechanisms of traditional Chinese medicine in insomnia treatment, highlighting astrocytic regulation as a potential therapeutic target.