Untargeted plasma metabolomics reveals systemic metabolic dysregulation and reatment-associated metabolic modulation following YWKS treatment in sleep disorder patients.

Sleep disorders are common and significantly impact metabolic regulation, but the overarching blood metabolomic characteristics and how drugs for these disorders affect metabolism have not been adequately described. Blood plasma from three distinct cohorts-healthy individuals, sleep disorder patients (SDP), and those undergoing YWKS pharmacological therapy (SDPM)-was analyzed using untargeted metabolomics (LC-MS/MS). Following quality control, 352 metabolites representing 21 chemical groups were kept, and a combination of differential analysis, multi-omics enrichment, and correlation networks was used to describe metabolic changes and how they reacted to treatment. In contrast to the control group, in patients with SDP, 173 metabolites showed significant dysregulation (121 up, 52 down). Evidence from this initial population indicated that YWKS therapy was correlated with the treatment-associated modulation of 119 of the 352 identified metabolic markers, while 54 remained in a state of imbalance, suggesting that therapeutic coverage was only partially achieved in this restricted sample size. Our study identified five putative metabolic axes encompassing purine degradation and oxidative stress, imbalances in the tryptophan-serotonin circuit, compromised mitochondrial fatty acid β-oxidation, the nexus of glycerophospholipid restructuring and neuroinflammation, and the induction of the renin-angiotensin system. These associations provide a hypothetical framework for understanding metabolic dysregulation in sleep disorders and warrant further mechanistic investigation. Through KEGG enrichment analysis, several vital metabolic routes were underscored, notably those involving glycerophospholipids, arachidonic acid signaling, and nucleotides. These findings suggest that sleep disturbances are associated with a complex metabolic imprint within the bloodstream that is not fully resolved by YWKS therapy. The continued presence of long-chain acylcarnitines in the SDPM group indicates ongoing mitochondrial dysfunction, suggesting that mitochondrial-targeted strategies warrant further exploratory investigation as potential adjuncts in the management of sleep disorders.