A Rhodiola-derived acidic glycopeptide maintains sleep homeostasis by regulating brain lipid metabolism in Drosophila

Sleep deprivation is closely associated with metabolic dysregulation, yet effective preventive interventions remain limited. Although Rhodiola rosea (R. rosea) exhibits promising sleep-modulating potential, the specific active components mediating its effects and the underlying mechanisms remain poorly elucidated.

This study aimed to identify the sleep-regulatory component of R. rosea and elucidate its molecular mechanism.

A bioactivity-guided fractionation strategy was applied using a sleep-deprived Drosophila melanogaster model. The active fraction was purified and structurally characterized by chromatographic separation and spectroscopic analyses. Sleep behavior, circadian rhythmicity, oxidative stress indices, neurotransmitter levels, lipid metabolic parameters, and brain transcriptomic profiles were systematically evaluated. Mechanistic validation was performed using neuronal genetic manipulation and dual-luciferase reporter assays targeting lipid metabolism-related pathways.

An acidic glycopeptide fraction derived from R. rosea (WRPA, 76 kDa) markedly increased total sleep duration by approximately 20%, reduced sleep fragmentation by approximately 20%, and improved circadian stability, locomotor activity, and cognitive performance in sleep-deprived flies. WRPA significantly alleviated oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels and restoring antioxidant capacity, while normalizing gamma-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) levels in the brain. Transcriptomic analysis revealed lipid metabolism as the primary pathway modulated by WRPA, with acetyl-CoA carboxylase (ACC) identified as a key target. WRPA suppressed ACC expression by inhibiting sterol regulatory element-binding protein (SREBP)-mediated transcription, leading to decreased triglyceride, cholesterol, and free fatty acid accumulation. Importantly, WRPA effectively rescued sleep disturbances induced by neuronal ACC overexpression, confirming an SREBP/ACC-dependent mechanism.

WRPA is identified as a novel sleep-regulatory acidic glycopeptide derived from R. rosea, which restores sleep homeostasis by maintaining lipid metabolic stability through the SREBP-ACC signaling axis. These findings expand the pharmacological repertoire of R. rosea beyond small molecules and highlight glycopeptides as promising lead candidates for metabolic sleep disorder intervention.