Isobicyclogermacrenal ameliorates hippocampal ferroptosis involvement in neurochemical disruptions and neuroinflammation induced by sleep deprivation in rats

•Natural extract isobicyclogermacrenal from Valeriana officinalis improves cognitive impairment and nerve damage caused by sleep deprivation.•Isobicyclogermacrenal mitigates neurotransmitter imbalances and reduces histopathological abnormalities in brain CA1 region.•Multiple-omics studies revealed isobicyclogermacrenal reduces neuronal ferroptosis and neuroinflammation associated with sleep deprivation.•Isobicyclogermacrenal offers a potential strategy to counteract sleep deprivation-induced impairment of neural function. Sleep deprivation (SLD) is a widespread condition that disrupts physiological functions and may increase mortality risk. Valeriana officinalis, a traditional medicinal herb known for its sedative and hypnotic properties, contains isobicyclogermacrenal (IG), a newly isolated active compound. However, research on the therapeutic potential of IG for treating SLD remains limited. In this study, IG was extracted and characterized from Valeriana officinalis, and an SLD model was established in rats using p-chlorophenylalanine (PCPA). Behavioral tests and pathological studies were conducted to assess the effects of IG on SLD, and transcriptomic and metabolomic analyses were utilized to investigate its underlying mechanisms. IG administration significantly improved the cognitive performance of SLD rats in behavioral tests and ameliorated histological injuries in the hippocampus and cerebral cortex. IG treatment increased the levels of brain-derived neurotrophic factor (BDNF) and neurotransmitters such as serotonin (5-HT) in SLD rats. Additionally, IG directly targets TFRC, thereby improving iron metabolism in the hippocampus. Comprehensive transcriptomic and metabolomic analyses revealed that the improvements from IG stemmed from the mitigation of abnormalities in iron metabolism, cholesterol metabolism, and glutathione metabolism, leading to reduced oxidative stress, ferroptosis, and neuroinflammation in the hippocampus caused by SLD. Collectively, these findings suggest that IG has the potential to ameliorate neurological damage and cognitive impairment caused by SLD, offering a novel strategy for protection against the adverse effects of SLD. Integrated transcriptomics and metabolomics analyses reveal the effect of isobicyclogermacrenal on ferroptosis involvement in neurotransmitter disorders and hippocampal injury induced by sleep deprivation in rats. [Display omitted]